MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Genes and Development' source. Thu, 09 Feb 2012 09:43:35 +0100 http://www.medworm.com/index.php?rid=5654642&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F3%2F294%3Frss%3D1 A wealth of genetic information and some biochemical analysis have made the GAL regulon of the yeast Saccharomyces cerevisiae a classic model system for studying transcriptional activation in eukaryotes. Galactose induces this transcriptional switch, which is regulated by three proteins: the transcriptional activator Gal4p, bound to DNA; the repressor Gal80p; and the transducer Gal3p. We showed previously that NADP appears to act as a trigger to kick the repressor off the activator. Sustained activation involves a complex of the transducer Gal3p and Gal80p mediated by galactose and ATP. We solved the crystal structure of the complex of Gal3p–Gal80p with α-D-galactose and ATP to 2.1 Å resolution. The interaction between the proteins occurs only when Gal3p is in a "closed" ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5654642 Wed, 01 Feb 2012 05:00:00 +0100 5654642 http://www.medworm.com/index.php?rid=5654641&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F3%2F282%3Frss%3D1 To find new genes that influence liver lipid mass, we performed a genetic screen for zebrafish mutants with hepatic steatosis, a pathological accumulation of fat. The red moon (rmn) mutant develops hepatic steatosis as maternally deposited yolk is depleted. Conversely, hepatic steatosis is suppressed in rmn mutants by adequate nutrition. Adult rmn mutants show increased liver neutral lipids and induction of hepatic lipid biosynthetic genes when fasted. Positional cloning of the rmn locus reveals a loss-of-function mutation in slc16a6a (solute carrier family 16a, member 6a), a gene that we show encodes a transporter of the major ketone body β-hydroxybutyrate. Restoring wild-type zebrafish slc16a6a expression or introducing human SLC16A6 in rmn mutant livers rescues the mutant phenotype... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5654641 Wed, 01 Feb 2012 05:00:00 +0100 5654641 http://www.medworm.com/index.php?rid=5654640&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F3%2F271%3Frss%3D1 Certain white adipose tissue (WAT) depots are readily able to convert to a "brown-like" state with prolonged cold exposure or exposure to β-adrenergic compounds. This process is characterized by the appearance of pockets of uncoupling protein 1 (UCP1)-positive, multilocular adipocytes and serves to increase the thermogenic capacity of the organism. We show here that fibroblast growth factor 21 (FGF21) plays a physiologic role in this thermogenic recruitment of WATs. In fact, mice deficient in FGF21 display an impaired ability to adapt to chronic cold exposure, with diminished browning of WAT. Adipose-derived FGF21 acts in an autocrine/paracrine manner to increase expression of UCP1 and other thermogenic genes in fat tissues. FGF21 regulates this process, at least in part, by enhancing... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5654640 Wed, 01 Feb 2012 05:00:00 +0100 5654640 http://www.medworm.com/index.php?rid=5654639&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F3%2F259%3Frss%3D1 Dietary obesity is a major factor in the development of type 2 diabetes and is associated with intra-adipose tissue hypoxia and activation of hypoxia-inducible factor 1α (HIF1α). Here we report that, in mice, Hif1α activation in visceral white adipocytes is critical to maintain dietary obesity and associated pathologies, including glucose intolerance, insulin resistance, and cardiomyopathy. This function of Hif1α is linked to its capacity to suppress β-oxidation, in part, through transcriptional repression of sirtuin 2 (Sirt2) NAD+-dependent deacetylase. Reduced Sirt2 function directly translates into diminished deacetylation of PPAR coactivator 1α (Pgc1α) and expression of β-oxidation and mitochondrial genes. Importantly, visceral adipose tiss... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5654639 Wed, 01 Feb 2012 05:00:00 +0100 5654639 http://www.medworm.com/index.php?rid=5654638&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F3%2F247%3Frss%3D1 Synapses are the fundamental units of neural circuits that enable complex behaviors. The neuromuscular junction (NMJ), a synapse formed between a motoneuron and a muscle fiber, has contributed greatly to understanding of the general principles of synaptogenesis as well as of neuromuscular disorders. NMJ formation requires neural agrin, a motoneuron-derived protein, which interacts with LRP4 (low-density lipoprotein receptor-related protein 4) to activate the receptor tyrosine kinase MuSK (muscle-specific kinase). However, little is known of how signals are transduced from agrin to MuSK. Here, we present the first crystal structure of an agrin–LRP4 complex, consisting of two agrin–LRP4 heterodimers. Formation of the initial binary complex requires the z8 loop that is specificall... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5654638 Wed, 01 Feb 2012 05:00:00 +0100 5654638 http://www.medworm.com/index.php?rid=5654637&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F3%2F241%3Frss%3D1 In fission yeast, the DNA damage sensor kinases Tel1ATM and Rad3ATR exist at telomeres and are required for telomere maintenance, but the biological role they play at telomeres is not known. Here we show that the telomere protein Ccq1 is phosphorylated at Thr 93 (threonine residue at amino acid 93) by Tel1ATM and Rad3ATR both in vitro and in vivo. A ccq1 mutant in which alanine was substituted for Thr 93 failed to recruit telomerase to telomeres and showed gradual shortening of telomeres. These results indicate that the direct phosphorylation of Ccq1 Thr 93 by Tel1 and Rad3 is involved in the recruitment of telomerase to elongate telomeres. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5654637 Wed, 01 Feb 2012 05:00:00 +0100 5654637 http://www.medworm.com/index.php?rid=5654636&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F3%2F235%3Frss%3D1 Protein poly(ADP-ribosyl)ation and ubiquitination are two key post-translational modifications regulating many biological processes. Through crystallographic and biochemical analysis, we show that the RNF146 WWE domain recognizes poly(ADP-ribose) (PAR) by interacting with iso-ADP-ribose (iso-ADPR), the smallest internal PAR structural unit containing the characteristic ribose–ribose glycosidic bond formed during poly(ADP-ribosyl)ation. The key iso-ADPR-binding residues we identified are highly conserved among WWE domains. Binding assays further demonstrate that PAR binding is a common function for the WWE domain family. Since many WWE domain-containing proteins are known E3 ubiquitin ligases, our results suggest that protein poly(ADP-ribosyl)ation may be a general mechanism to target... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5654636 Wed, 01 Feb 2012 05:00:00 +0100 5654636 http://www.medworm.com/index.php?rid=5654635&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F3%2F203%3Frss%3D1 The ability to sense and adjust to the environment is crucial to life. For multicellular organisms, the ability to respond to external changes is essential not only for survival but also for normal development and physiology. Although signaling events can directly modify cellular function, typically signaling acts to alter transcriptional responses to generate both transient and sustained changes. Rapid, but transient, changes in gene expression are mediated by inducible transcription factors such as NF-B. For the past 25 years, NF-B has served as a paradigm for inducible transcription factors and has provided numerous insights into how signaling events influence gene expression and physiology. Since its discovery as a regulator of expression of the light chain gene in B cells, research on... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5654635 Wed, 01 Feb 2012 05:00:00 +0100 5654635 http://www.medworm.com/index.php?rid=5633750&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F2%2F190%3Frss%3D1 In response to skeletal muscle injury, satellite cells, which function as a myogenic stem cell population, become activated, expand through proliferation, and ultimately fuse with each other and with damaged myofibers to promote muscle regeneration. Here, we show that members of the Myocardin family of transcriptional coactivators, MASTR and MRTF-A, are up-regulated in satellite cells in response to skeletal muscle injury and muscular dystrophy. Global and satellite cell-specific deletion of MASTR in mice impairs skeletal muscle regeneration. This impairment is substantially greater when MRTF-A is also deleted and is due to aberrant differentiation and excessive proliferation of satellite cells. These abnormalities mimic those associated with genetic deletion of MyoD, a master regulator of... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5633750 Wed, 25 Jan 2012 05:00:00 +0100 5633750 http://www.medworm.com/index.php?rid=5633749&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F2%2F176%3Frss%3D1 In this study, we reveal that IGF2BP1 promotes the velocity and directionality of tumor-derived cell migration by determining the cytoplasmic fate of two novel target mRNAs: MAPK4 and PTEN. Inhibition of MAPK4 mRNA translation by IGF2BP1 antagonizes MK5 activation and prevents phosphorylation of HSP27, which sequesters actin monomers available for F-actin polymerization. Consequently, HSP27–ACTB association is reduced, mobilizing cellular G-actin for polymerization in order to promote the velocity of cell migration. At the same time, stabilization of the PTEN mRNA by IGF2BP1 enhances PTEN expression and antagonizes PIP3-directed signaling. This enforces the directionality of cell migration in a RAC1-dependent manner by preventing additional lamellipodia from forming and sustaining ce... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5633749 Wed, 25 Jan 2012 05:00:00 +0100 5633749 http://www.medworm.com/index.php?rid=5633748&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F2%2F163%3Frss%3D1 Genome instability via RNA:DNA hybrid-mediated R loops has been observed in mutants involved in various aspects of transcription and RNA processing. The prevalence of this mechanism among essential chromosome instability (CIN) genes remains unclear. In a secondary screen for increased Rad52 foci in CIN mutants, representing ~25% of essential genes, we identified seven essential subunits of the mRNA cleavage and polyadenylation (mCP) machinery. Genome-wide analysis of fragile sites by chromatin immunoprecipitation (ChIP) and microarray (ChIP–chip) of phosphorylated H2A in these mutants supported a transcription-dependent mechanism of DNA damage characteristic of R loops. In parallel, we directly detected increased RNA:DNA hybrid formation in mCP mutants and demonstrated that CIN is su... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5633748 Wed, 25 Jan 2012 05:00:00 +0100 5633748 http://www.medworm.com/index.php?rid=5633747&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F2%2F151%3Frss%3D1 SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like1) maintains genome integrity during DNA replication. Here we investigated its mechanism of action. We found that SMARCAL1 travels with elongating replication forks, and its absence leads to MUS81-dependent double-strand break formation. Binding to specific nucleic acid substrates activates SMARCAL1 activity in a reaction that requires its HARP2 (Hep-A-related protein 2) domain. Homology modeling indicates that the HARP domain is similar in structure to the DNA-binding domain of the PUR proteins. Limited proteolysis, small-angle X-ray scattering, and functional assays indicate that the core enzymatic unit consists of the HARP2 and ATPase domains that fold into a stable structure. Surprisin... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5633747 Wed, 25 Jan 2012 05:00:00 +0100 5633747 http://www.medworm.com/index.php?rid=5633746&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F2%2F137%3Frss%3D1 One of the long-standing questions in eukaryotic DNA replication is the mechanisms that determine where and when a particular segment of the genome is replicated. Cdc7/Hsk1 is a conserved kinase required for initiation of DNA replication and may affect the site selection and timing of origin firing. We identified rif1, a null mutant of rif1+, a conserved telomere-binding factor, as an efficient bypass mutant of fission yeast hsk1. Extensive deregulation of dormant origins over a wide range of the chromosomes occurs in rif1 in the presence or absence of hydroxyurea (HU). At the same time, many early-firing, efficient origins are suppressed or delayed in firing timing in rif1. Rif1 binds not only to telomeres, but also to many specific locations on the arm segments that only partially overla... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5633746 Wed, 25 Jan 2012 05:00:00 +0100 5633746 http://www.medworm.com/index.php?rid=5633745&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F2%2F126%3Frss%3D1 Valves on the plant epidermis called stomata develop according to positional cues, which likely involve putative ligands (EPIDERMAL PATTERNING FACTORS [EPFs]) and putative receptors (ERECTA family receptor kinases and TOO MANY MOUTHS [TMM]) in Arabidopsis. Here we report the direct, robust, and saturable binding of bioactive EPF peptides to the ERECTA family. In contrast, TMM exhibits negligible binding to EPF1 but binding to EPF2. The ERECTA family forms receptor homomers in vivo. On the other hand, TMM associates with the ERECTA family but not with itself. While ERECTA family receptor kinases exhibit complex redundancy, blocking ERECTA and ERECTA-LIKE1 (ERL1) signaling confers specific insensitivity to EPF2 and EPF1, respectively. Our results place the ERECTA family as the primary recept... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5633745 Wed, 25 Jan 2012 05:00:00 +0100 5633745 http://www.medworm.com/index.php?rid=5633744&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F2%2F120%3Frss%3D1 Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-xL and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-xL, Bcl-2, or Bcl-w, caused the death of transformed AML and could cure disease in AML-afflicted mice. Enforced expression of selective inhibitors of prosurvival Bcl-2 family members revealed that Mcl-1 is critical for survival of human AML cells. Thus, targeting of Mcl-1 or regulators of its expression may be a useful strategy for the treatment of AML. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5633744 Wed, 25 Jan 2012 05:00:00 +0100 5633744 http://www.medworm.com/index.php?rid=5633743&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F2%2F114%3Frss%3D1 Protein lysine methylation is one of the most widespread post-translational modifications in the nuclei of eukaryotic cells. Methylated lysines on histones and nonhistone proteins promote the formation of protein complexes that control gene expression and DNA replication and repair. In the cytoplasm, however, the role of lysine methylation in protein complex formation is not well established. Here we report that the cytoplasmic protein chaperone Hsp90 is methylated by the lysine methyltransferase Smyd2 in various cell types. In muscle, Hsp90 methylation contributes to the formation of a protein complex containing Smyd2, Hsp90, and the sarcomeric protein titin. Deficiency in Smyd2 results in the loss of Hsp90 methylation, impaired titin stability, and altered muscle function. Collectively, ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5633743 Wed, 25 Jan 2012 05:00:00 +0100 5633743 http://www.medworm.com/index.php?rid=5633742&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F2%2F110%3Frss%3D1 RNA-binding proteins (RBPs) exert many roles in the post-transcriptional regulation of gene expression in eukaryotic cells. However, our understanding of how they recognize their target RNAs in vivo remains limited. In the January 1, 2012, issue of Genes & Development, Patel and colleagues (p. 43–53) provide detailed mechanistic insights into how one of the best-studied RBPs, zipcode-binding protein 1 (ZBP1), recognizes a bipartite RNA sequence element within the β-actin mRNA. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5633742 Wed, 25 Jan 2012 05:00:00 +0100 5633742 http://www.medworm.com/index.php?rid=5633741&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F2%2F105%3Frss%3D1 In a study in the December 15, 2011, issue of Genes & Development, Valenta and colleagues (pp. 2631–2643) constructed a series of β-catenin mutants that allowed them to separate β-catenin's activity as a mediator of Wnt signaling from its activity as cell adhesion component. In doing so, they uncovered some surprising properties of Wnt signaling. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5633741 Wed, 25 Jan 2012 05:00:00 +0100 5633741 http://www.medworm.com/index.php?rid=5567038&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F1%2F92%3Frss%3D1 We present the structures of two type I RM enzymes, EcoKI and EcoR124I, derived using electron microscopy (EM), small-angle scattering (neutron and X-ray), and detailed molecular modeling. DNA binding triggers a large contraction of the open form of the enzyme to a compact form. The path followed by DNA through the complexes is revealed by using a DNA mimic anti-restriction protein. The structures reveal an evolutionary link between type I RM enzymes and type II RM enzymes. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5567038 Tue, 03 Jan 2012 05:00:00 +0100 5567038 http://www.medworm.com/index.php?rid=5567037&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F1%2F82%3Frss%3D1 The telomerase protein Est1 exists in multiple organisms, including Schizosaccharomyces pombe, humans, and Saccharomyces cerevisiae, but its function has only been closely examined in S. cerevisiae, where it is a recruiter/activator of telomerase. Here, we demonstrate that S. pombe Est1 was required for the telomere association of the telomerase holoenzyme, suggesting that it too has a recruitment role. Its association with telomeres was dependent on Trt1, the catalytic subunit, and Ccq1, a telomeric protein. Surprisingly, Est1 telomere binding was only partially dependent on TER1, the telomerase RNA, even though Est1 bound nucleotides 415–507 of TER1. A ter1-415–507 strain had short telomeres and very low Est1 and Trt1 telomere association in late S phase but did not senesce. ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5567037 Tue, 03 Jan 2012 05:00:00 +0100 5567037 http://www.medworm.com/index.php?rid=5567036&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F1%2F69%3Frss%3D1 Hirschsprung disease (HSCR) is caused by a reduction of enteric neural crest cells (ENCCs) in the gut and gastrointestinal blockage. Knowledge of the genetics underlying HSCR is incomplete, particularly genes that control cellular behaviors of ENCC migration. Here we report a novel regulator of ENCC migration in mice. Disruption of the Phactr4 gene causes an embryonic gastrointestinal defect due to colon hypoganglionosis, which resembles human HSCR. Time-lapse imaging of ENCCs within the embryonic gut demonstrates a collective cell migration defect. Mutant ENCCs show undirected cellular protrusions and disrupted directional and chain migration. Phactr4 acts cell-autonomously in ENCCs and colocalizes with integrin and cofilin at cell protrusions. Mechanistically, we show that Phactr4 negati... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5567036 Tue, 03 Jan 2012 05:00:00 +0100 5567036 http://www.medworm.com/index.php?rid=5567035&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F1%2F54%3Frss%3D1 Cell attachment to the extracellular matrix (ECM) is crucial to cell physiology such as polarity, motility, and proliferation. In normal cells, loss of attachment to the ECM induces a specific type of apoptosis, termed anoikis. Resistance to anoikis in cancer cells promotes their survival in circulation and dispersion to distant anatomic sites, leading to tumor metastasis. The Yes-associated protein (YAP) transcription coactivator is a human oncogene and a key regulator of organ size. The Hippo tumor suppressor pathway phosphorylates and inhibits YAP. However, little is known about the signals that regulate the Hippo pathway. Here we report that through cytoskeleton reorganization, cell detachment activates the Hippo pathway kinases Lats1/2 and leads to YAP phosphorylation and inhibition. ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5567035 Tue, 03 Jan 2012 05:00:00 +0100 5567035 http://www.medworm.com/index.php?rid=5567034&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F1%2F43%3Frss%3D1 In this study, we demonstrate that specific recognition of messenger RNAs (mRNAs) by RNA-binding proteins requires the correct spatial positioning of these sequences. We characterized both the cis-acting sequence elements and the spatial restraints that define the mode of RNA binding of the zipcode-binding protein 1 (ZBP1/IMP1/IGF2BP1) to the β-actin zipcode. The third and fourth KH (hnRNP K homology) domains of ZBP1 specifically recognize a bipartite RNA element comprised of a 5' element (CGGAC) followed by a variable 3' element (C/A-CA-C/U) that must be appropriately spaced. Remarkably, the orientation of these elements is interchangeable within target transcripts bound by ZBP1. The spatial relationship of this consensus binding site identified conserved transcripts that were verifi... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5567034 Tue, 03 Jan 2012 05:00:00 +0100 5567034 http://www.medworm.com/index.php?rid=5567033&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F1%2F37%3Frss%3D1 Polycomb-repressive complex 2 (PRC2) promotes tissue-specific differentiation by depositing trimethylated histone H3 Lys 27 (H3K27me3) epigenetic marks to silence ectopic gene expression programs. Here, we show that EZH2, the catalytic subunit of PRC2, is required for cardiac morphogenesis. Both in vitro and in fetal hearts, EZH2 interacted with cardiac transcription factor GATA4 and directly methylated it at Lys 299. PRC2 methylation of GATA4 attenuated its transcriptional activity by reducing its interaction with and acetylation by p300. Our results reveal a new mechanism of PRC2-mediated transcriptional repression in which PRC2 methylates a transcription factor to inhibit its transcriptional activity. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5567033 Tue, 03 Jan 2012 05:00:00 +0100 5567033 http://www.medworm.com/index.php?rid=5567032&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F1%2F31%3Frss%3D1 Proper development requires coordination in growth of the cell types composing an organ. Many plant and animal cells are polyploid, but how these polyploid tissues contribute to organ growth is not well understood. We found the Drosophila melanogaster subperineurial glia (SPG) to be polyploid, and ploidy is coordinated with brain mass. Inhibition of SPG polyploidy caused rupture of the septate junctions necessary for the blood–brain barrier. Thus, the increased SPG cell size resulting from polyploidization is required to maintain the SPG envelope surrounding the growing brain. Polyploidization likely is a conserved strategy to coordinate tissue growth during organogenesis, with potential vertebrate examples. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5567032 Tue, 03 Jan 2012 05:00:00 +0100 5567032 http://www.medworm.com/index.php?rid=5567031&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F1%2F25%3Frss%3D1 Differentiation of neural stem cells (NSCs) to neurons requires the activation of genes controlled by the repressor element 1 (RE1) silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) protein complex. Important components of REST/NRSF are phosphatases (termed RNA polymerase II C-terminal domain small phosphatases [CTDSPs]) that inhibit RNA polymerase II and suppress neuronal gene expression in NSCs. Activation of genes controlled by CTDSPs is required for neurogenesis, but how this is achieved is not fully understood. Here we show that ctdsp2 is a target of miR-26b, a microRNA that is encoded in an intron of the ctdsp2 primary transcript. This intrinsic negative feedback loop is inactive in NSCs because miR-26b biogenesis is inhibited at the precursor level. Gen... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5567031 Tue, 03 Jan 2012 05:00:00 +0100 5567031 http://www.medworm.com/index.php?rid=5567030&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F1%2F11%3Frss%3D1 Over the past 10 years, the development of chromosome conformation capture (3C) technology and the subsequent genomic variants thereof have enabled the analysis of nuclear organization at an unprecedented resolution and throughput. The technology relies on the original and, in hindsight, remarkably simple idea that digestion and religation of fixed chromatin in cells, followed by the quantification of ligation junctions, allows for the determination of DNA contact frequencies and insight into chromosome topology. Here we evaluate and compare the current 3C-based methods (including 4C [chromosome conformation capture-on-chip], 5C [chromosome conformation capture carbon copy], HiC, and ChIA-PET), summarize their contribution to our current understanding of genome structure, and discuss how s... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5567030 Tue, 03 Jan 2012 05:00:00 +0100 5567030 http://www.medworm.com/index.php?rid=5567029&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F1%2F6%3Frss%3D1 Differentiation of multipotent stem cells occurs through the highly coordinated control of gene expression. Repressor element 1 (RE1) silencing transcription factor (REST), a master transcriptional regulator in neuronal stem cells, restricts neuronal gene expression. REST activity is context-dependent and is modified by its cofactors, such as Ctdsp2. In this issue of Genes & Development, Dill and colleagues (pp. 25–30) report on the microRNA-mediated regulation of neural differentiation. Interestingly, this microRNA is post-transcriptionally regulated and modulates expression of its host gene, ctdsp2. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5567029 Tue, 03 Jan 2012 05:00:00 +0100 5567029 http://www.medworm.com/index.php?rid=5567028&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F26%2F1%2F1%3Frss%3D1 β1 integrin signaling plays crucial roles in enteric nervous system development. Zhang and colleagues (pp. 69–81) discovered that phosphatase and actin regulator 4 (Phactr4) antagonizes β1 integrin signaling through protein phosphatase 1 (PP1) in focal adhesions of enteric neural crest cells (ENCCs). Loss of Phactr4–PP1 interaction leads to increased β1 integrin signaling, loss of collective and directional migration, and hindgut hypogangaliosis, indicating that the right adjustment of β1 integrin signaling is required for the normal migration and organization of ENCCs. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5567028 Tue, 03 Jan 2012 05:00:00 +0100 5567028 http://www.medworm.com/index.php?rid=5531260&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2690%3Frss%3D1 (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531260 Wed, 21 Dec 2011 05:00:00 +0100 5531260 http://www.medworm.com/index.php?rid=5531259&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2686%3Frss%3D1 (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531259 Wed, 21 Dec 2011 05:00:00 +0100 5531259 http://www.medworm.com/index.php?rid=5531258&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2674%3Frss%3D1 We report that knockout of the activity-regulated gene cpg15 in mice delays developmental maturation of axonal and dendritic arbors visualized by anterograde tracing and diolistic labeling, respectively. Electrophysiology shows that synaptic maturation is also delayed, and electron microscopy confirms that many dendritic spines initially lack functional synaptic contacts. While circuits eventually develop, in vivo imaging reveals that spine maintenance is compromised in the adult, leading to a gradual attrition in spine numbers. Loss of cpg15 also results in poor learning. cpg15 knockout mice require more trails to learn, but once they learn, memories are retained. Our findings suggest that CPG15 acts to stabilize active synapses on dendritic spines, resulting in selective spine and arbor ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531258 Wed, 21 Dec 2011 05:00:00 +0100 5531258 http://www.medworm.com/index.php?rid=5531257&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2659%3Frss%3D1 Transient receptor potential (TRP) channels have been implicated as sensors of diverse stimuli in mature neurons. However, developmental roles for TRP channels in the establishment of neuronal connectivity remain largely unexplored. Here, we identify an essential function for TRPC5, a member of the canonical TRP subfamily, in the regulation of dendrite patterning in the mammalian brain. Strikingly, TRPC5 knockout mice harbor long, highly branched granule neuron dendrites with impaired dendritic claw differentiation in the cerebellar cortex. In vivo RNAi analyses suggest that TRPC5 regulates dendrite morphogenesis in the cerebellar cortex in a cell-autonomous manner. Correlating with impaired dendrite patterning in the cerebellar cortex, behavioral analyses reveal that TRPC5 knockout mice h... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531257 Wed, 21 Dec 2011 05:00:00 +0100 5531257 http://www.medworm.com/index.php?rid=5531256&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2644%3Frss%3D1 Cancer stem cells (CSCs) are postulated to be a small subset of tumor cells with tumor-initiating ability that shares features with normal tissue-specific stem cells. The origin of CSCs and the mechanisms underlying their genesis are poorly understood, and it is uncertain whether it is possible to obliterate CSCs without inadvertently damaging normal stem cells. Here we show that a functional reduction of eukaryotic translation initiation factor 4E (eIF4E) in Drosophila specifically eliminates CSC-like cells in the brain and ovary without having discernable effects on normal stem cells. Brain CSC-like cells can arise from dedifferentiation of transit-amplifying progenitors upon Notch hyperactivation. eIF4E is up-regulated in these dedifferentiating progenitors, where it forms a feedback re... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531256 Wed, 21 Dec 2011 05:00:00 +0100 5531256 http://www.medworm.com/index.php?rid=5531255&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2631%3Frss%3D1 β-Catenin, apart from playing a cell-adhesive role, is a key nuclear effector of Wnt signaling. Based on activity assays in Drosophila, we generated mouse strains where the endogenous β-catenin protein is replaced by mutant forms, which retain the cell adhesion function but lack either or both of the N- and the C-terminal transcriptional outputs. The C-terminal activity is essential for mesoderm formation and proper gastrulation, whereas N-terminal outputs are required later during embryonic development. By combining the double-mutant β-catenin with a conditional null allele and a Wnt1-Cre driver, we probed the role of Wnt/β-catenin signaling in dorsal neural tube development. While loss of β-catenin protein in the neural tube results in severe cell adhesion defect... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531255 Wed, 21 Dec 2011 05:00:00 +0100 5531255 http://www.medworm.com/index.php?rid=5531254&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2619%3Frss%3D1 To identify new gene regulatory pathways controlling skeletal muscle energy metabolism, comparative studies were conducted on muscle-specific transgenic mouse lines expressing the nuclear receptors peroxisome proliferator-activated receptor α (PPARα; muscle creatine kinase [MCK]-PPARα) or PPARβ/ (MCK-PPARβ/). MCK-PPARβ/ mice are known to have enhanced exercise performance, whereas MCK-PPARα mice perform at low levels. Transcriptional profiling revealed that the lactate dehydrogenase b (Ldhb)/Ldha gene expression ratio is increased in MCK-PPARβ/ muscle, an isoenzyme shift that diverts pyruvate into the mitochondrion for the final steps of glucose oxidation. PPARβ/ gain- and loss-of-function studies in skeletal myotubes demonstrated that PPAR&... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531254 Wed, 21 Dec 2011 05:00:00 +0100 5531254 http://www.medworm.com/index.php?rid=5531253&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2610%3Frss%3D1 Histone deacetylases (HDACs) are major epigenetic modulators involved in a broad spectrum of human diseases including cancers. Administration of HDAC inhibitors (HDACis) leads to growth inhibition, differentiation, and apoptosis of cancer cells. Understanding the regulatory mechanism of HDACs is imperative to harness the therapeutic potentials of HDACis. Here we show that HDACi- and DNA damage-induced apoptosis are severely compromised in mouse embryonic fibroblasts lacking a HECT domain ubiquitin ligase, Mule (Mcl-1 ubiquitin ligase E3). Mule specifically targets HDAC2 for ubiquitination and degradation. Accumulation of HDAC2 in Mule-deficient cells leads to compromised p53 acetylation as well as crippled p53 transcriptional activation, accumulation, and apoptotic response upon DNA damage... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531253 Wed, 21 Dec 2011 05:00:00 +0100 5531253 http://www.medworm.com/index.php?rid=5531252&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2594%3Frss%3D1 Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) gene expression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis of available expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified the transcriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZ expression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with MES GBMs. Silencing of TAZ in MES glioma stem cells (GSCs) decreased expression of MES markers, invasion, self-renewal, and tumor formation. Conversely, overexpression of TAZ in PN GSCs as well as murine neu... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531252 Wed, 21 Dec 2011 05:00:00 +0100 5531252 http://www.medworm.com/index.php?rid=5531251&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2579%3Frss%3D1 Nuclear lamin B1 (LB1) is a major structural component of the nucleus that appears to be involved in the regulation of many nuclear functions. The results of this study demonstrate that LB1 expression in WI-38 cells decreases during cellular senescence. Premature senescence induced by oncogenic Ras also decreases LB1 expression through a retinoblastoma protein (pRb)-dependent mechanism. Silencing the expression of LB1 slows cell proliferation and induces premature senescence in WI-38 cells. The effects of LB1 silencing on proliferation require the activation of p53, but not pRb. However, the induction of premature senescence requires both p53 and pRb. The proliferation defects induced by silencing LB1 are accompanied by a p53-dependent reduction in mitochondrial reactive oxygen species (RO... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531251 Wed, 21 Dec 2011 05:00:00 +0100 5531251 http://www.medworm.com/index.php?rid=5531250&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2573%3Frss%3D1 Long noncoding RNAs (lncRNAs) are differentially expressed under both normal and pathological conditions, implying that they may play important biological functions. Here we examined the expression of lncRNAs during erythropoiesis and identified an erythroid-specific lncRNA with anti-apoptotic activity. Inhibition of this lncRNA blocks erythroid differentiation and promotes apoptosis. Conversely, ectopic expression of this lncRNA can inhibit apoptosis in mouse erythroid cells. This lncRNA represses expression of Pycard, a proapoptotic gene, explaining in part the inhibition of programmed cell death. These findings reveal a novel layer of regulation of cell differentiation and apoptosis by a lncRNA. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531250 Wed, 21 Dec 2011 05:00:00 +0100 5531250 http://www.medworm.com/index.php?rid=5531249&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2559%3Frss%3D1 Leukocytes and their soluble mediators play important regulatory roles in all aspects of solid tumor development. While immunotherapeutic strategies have conceptually held clinical promise, with the exception of a small percentage of patients, they have failed to demonstrate effective, consistent, and durable anti-cancer responses. Several subtypes of leukocytes that commonly infiltrate solid tumors harbor immunosuppressive activity and undoubtedly restrict the effectiveness of these strategies. Several of these same immune cells also foster tumor development by expression of potent protumor mediators. Given recent evidence revealing that immune-based mechanisms regulate the response to conventional cytotoxic therapy, it seems reasonable to speculate that tumor progression could be effecti... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531249 Wed, 21 Dec 2011 05:00:00 +0100 5531249 http://www.medworm.com/index.php?rid=5531248&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F24%2F2555%3Frss%3D1 Long noncoding RNAs (lncRNAs) are a large and diverse class of functional RNAs that regulate important biological processes, including cell division, survival, and differentiation. In this issue of Genes & Development, Hu and colleagues (2573–2578) report the discovery of LincRNA erythroid prosurvival (LincRNA-EPS), a murine lncRNA that facilitates red blood cell formation (erythropoiesis) by suppressing apoptosis. This finding expands the repertoire of lncRNA functions and illustrates a novel genetic pathway that potentially can be exploited for treating anemias. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5531248 Wed, 21 Dec 2011 05:00:00 +0100 5531248 http://www.medworm.com/index.php?rid=5481641&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F23%2F2540%3Frss%3D1 Legumes and many nonleguminous plants enter symbiotic interactions with microbes, and it is poorly understood how host plants respond to promote beneficial, symbiotic microbial interactions while suppressing those that are deleterious or pathogenic. Trans-acting siRNAs (tasiRNAs) negatively regulate target transcripts and are characterized by siRNAs spaced in 21-nucleotide (nt) "phased" intervals, a pattern formed by DICER-LIKE 4 (DCL4) processing. A search for phased siRNAs (phasiRNAs) found at least 114 Medicago loci, the majority of which were defense-related NB-LRR-encoding genes. We identified three highly abundant 22-nt microRNA (miRNA) families that target conserved domains in these NB-LRRs and trigger the production of trans-acting siRNAs. High levels of small RNAs were matched to ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5481641 Wed, 07 Dec 2011 05:00:00 +0100 5481641 http://www.medworm.com/index.php?rid=5481640&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F23%2F2525%3Frss%3D1 The yeast Tup1–Cyc8 corepressor complex is recruited to promoters by DNA-binding repressors, but the mechanisms by which it inhibits expression of genes involved in various stress pathways are poorly understood. Conditional and rapid depletion of Tup1 from the nucleus leads to concurrent nucleosome depletion and histone acetylation, recruitment of coactivators (Swi/Snf, SAGA, and Mediator), and increased transcriptional activity. Conversely, coactivator dissociation occurs rapidly upon rerepression by Cyc8–Tup1, although coactivator association and transcription can be blocked even in the absence of nucleosomes. The coactivators are recruited to the sites where Tup1 was located prior to depletion, indicating that the repressor proteins that recruit Tup1 function as activators i... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5481640 Wed, 07 Dec 2011 05:00:00 +0100 5481640 http://www.medworm.com/index.php?rid=5481639&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F23%2F2513%3Frss%3D1 The factors and mechanisms underlying the differential activity and regulation of eukaryotic RNA polymerase II on different types of core promoters have remained elusive. Here we show that the architectural factor HMGA1 and the Mediator coregulator complex cooperate to enhance basal transcription from core promoters containing both a TATA box and an Initiator (INR) element but not from "TATA-only" core promoters. INR-dependent activation by HMGA1 and Mediator requires the TATA-binding protein (TBP)-associated factors (TAFs) within the TFIID complex and counteracts negative regulators of TBP/TATA-dependent transcription such as NC2 and Topoisomerase I. HMGA1 interacts with TFIID and Mediator and is required for the synergy of TATA and INR elements in mammalian cells. Accordingly, natural HM... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5481639 Wed, 07 Dec 2011 05:00:00 +0100 5481639 http://www.medworm.com/index.php?rid=5481638&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F23%2F2502%3Frss%3D1 To determine the prevalence of cotranscriptional splicing in Drosophila, we sequenced nascent RNA transcripts from Drosophila S2 cells as well as from Drosophila heads. Eighty-seven percent of the introns assayed manifest >50% cotranscriptional splicing. The remaining 13% are cotranscriptionally spliced poorly or slowly, with ~3% being almost completely retained in nascent pre-mRNA. Although individual introns showed slight but statistically significant differences in splicing efficiency, similar global levels of splicing were seen from both sources. Importantly, introns with low cotranscriptional splicing efficiencies are present in the same primary transcript with efficiently spliced introns, indicating that splicing is intron-specific. The analysis also indicates that cotranscription... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5481638 Wed, 07 Dec 2011 05:00:00 +0100 5481638 http://www.medworm.com/index.php?rid=5481637&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F23%2F2489%3Frss%3D1 The cell cycle-regulated expression of core histone genes is required for DNA replication and proper cell cycle progression in eukaryotic cells. Although some factors involved in histone gene transcription are known, the molecular mechanisms that ensure proper induction of histone gene expression during S phase remain enigmatic. Here we demonstrate that S-phase transcription of the model histone gene HTA1 in yeast is regulated by a novel attach–release mechanism involving phosphorylation of the conserved chromatin boundary protein Yta7 by both cyclin-dependent kinase 1 (Cdk1) and casein kinase 2 (CK2). Outside S phase, integrity of the AAA-ATPase domain is required for Yta7 boundary function, as defined by correct positioning of the histone chaperone Rtt106 and the chromatin remodeli... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5481637 Wed, 07 Dec 2011 05:00:00 +0100 5481637 http://www.medworm.com/index.php?rid=5481636&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F23%2F2480%3Frss%3D1 Macrophages, a key cellular component of inflammation, become functionally polarized in a signal- and context-specific manner. Th2 cytokines such as interleukin 4 (IL-4) polarize macrophages to a state of alternative activation that limits inflammation and promotes wound healing. Alternative activation is mediated by a transcriptional program that is influenced by epigenomic modifications, including histone acetylation. Here we report that macrophages lacking histone deacetylase 3 (HDAC3) display a polarization phenotype similar to IL-4-induced alternative activation and, furthermore, are hyperresponsive to IL-4 stimulation. Throughout the macrophage genome, HDAC3 deacetylates histone tails at regulatory regions, leading to repression of many IL-4-regulated genes characteristic of alternat... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5481636 Wed, 07 Dec 2011 05:00:00 +0100 5481636 http://www.medworm.com/index.php?rid=5481635&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F23%2F2465%3Frss%3D1 This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5481635 Wed, 07 Dec 2011 05:00:00 +0100 5481635 http://www.medworm.com/index.php?rid=5481634&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F23%2F2453%3Frss%3D1 Pluripotent embryonic stem (ES) cells can generate all cell types, but how cell lineages are initially specified and maintained during development remains largely unknown. Different classes of Sox transcription factors are expressed during neurogenesis and have been assigned important roles from early lineage specification to neuronal differentiation. Here we characterize the genome-wide binding for Sox2, Sox3, and Sox11, which have vital functions in ES cells, neural precursor cells (NPCs), and maturing neurons, respectively. The data demonstrate that Sox factor binding depends on developmental stage-specific constraints and reveal a remarkable sequential binding of Sox proteins to a common set of neural genes. Interestingly, in ES cells, Sox2 preselects for neural lineage-specific genes ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5481634 Wed, 07 Dec 2011 05:00:00 +0100 5481634 http://www.medworm.com/index.php?rid=5481633&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F23%2F2436%3Frss%3D1 Ten-eleven translocation 1–3 (Tet1–3) proteins have recently been discovered in mammalian cells to be members of a family of DNA hydroxylases that possess enzymatic activity toward the methyl mark on the 5-position of cytosine (5-methylcytosine [5mC]), a well-characterized epigenetic modification that has essential roles in regulating gene expression and maintaining cellular identity. Tet proteins can convert 5mC into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) through three consecutive oxidation reactions. These modified bases may represent new epigenetic states in genomic DNA or intermediates in the process of DNA demethylation. Emerging biochemical, genetic, and functional evidence suggests that Tet proteins are crucial for diverse b... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5481633 Wed, 07 Dec 2011 05:00:00 +0100 5481633 http://www.medworm.com/index.php?rid=5481632&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F23%2F2429%3Frss%3D1 The Tup1–Cyc8 complex is responsible for repression of a large and diverse collection of genes in Saccharomyces cerevisiae. The predominant view has been that Tup1–Cyc8 functions as a corepressor, actively associating with regulatory proteins and organizing chromatin to block transcription. A new study by Wong and Struhl in this issue of Genes & Development (pp. 2525–2539) challenges nearly 20 years of models by demonstrating that Tup1–Cyc8 functions primarily as a shield to block DNA-binding proteins from recruiting transcriptional coactivators. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5481632 Wed, 07 Dec 2011 05:00:00 +0100 5481632 http://www.medworm.com/index.php?rid=5481631&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F23%2F2423%3Frss%3D1 Vertebrate embryonic stem (ES) cells give rise to many different cell types in multistep processes. These involve the establishment of a competent state, specification, differentiation, and maturation, and often involve Sox transcription factors. In this issue of Genes & Development, Bergsland and colleagues (pp. 2453–2464) determine the genome-wide binding profile of Sox2, Sox3, and Sox11 as ES cells become specified to neural precursors and differentiate into neurons. An ordered, sequential binding of these Sox proteins to a common set of gene enhancers was found to drive neurogenesis, as Sox proteins first help to preselect neural genes in ES cells and later ensure their proper activation in neural precursors or neurons. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5481631 Wed, 07 Dec 2011 05:00:00 +0100 5481631 http://www.medworm.com/index.php?rid=5415523&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F22%2F2409%3Frss%3D1 Box H/ACA ribonucleoprotein particles (RNPs) mediate pseudouridine synthesis, ribosome formation, and telomere maintenance. The structure of eukaryotic H/ACA RNPs remains poorly understood. We reconstituted functional Saccharomyces cerevisiae H/ACA RNPs with recombinant proteins Cbf5, Nop10, Gar1, and Nhp2 and a two-hairpin H/ACA RNA; determined the crystal structure of a Cbf5, Nop10, and Gar1 ternary complex at 1.9 Å resolution; and analyzed the structure–function relationship of the yeast complex. Although eukaryotic H/ACA RNAs have a conserved two-hairpin structure, isolated single-hairpin RNAs are also active in guiding pseudouridylation. Nhp2, unlike its archaeal counterpart, is largely dispensable for the activity, reflecting a functional adaptation of eukaryotic H/ACA RN... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5415523 Tue, 15 Nov 2011 05:00:00 +0100 5415523 http://www.medworm.com/index.php?rid=5415522&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F22%2F2398%3Frss%3D1 We report the crystal structure of the C-terminal domain of yeast SHQ1, Shq1p, and its complex with yeast dyskerin/NAP57, Cbf5p, lacking its catalytic domain. The C-terminal domain of Shq1p interacts with the RNA-binding domain of Cbf5p and, through structural mimicry, uses the RNA–protein-binding sites to achieve a specific protein–protein interface. We propose that Shq1p operates as a Cbf5p chaperone during RNP assembly by acting as an RNA placeholder, thereby preventing Cbf5p from nonspecific RNA binding before association with an H/ACA RNA and the other core RNP proteins. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5415522 Tue, 15 Nov 2011 05:00:00 +0100 5415522 http://www.medworm.com/index.php?rid=5415521&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F22%2F2387%3Frss%3D1 Heat shock rapidly induces expression of a subset of genes while globally repressing transcription, making it an attractive system to study alterations in the chromatin landscape that accompany changes in gene regulation. We characterized these changes in Drosophila cells by profiling classical low-salt-soluble chromatin, RNA polymerase II (Pol II), and nucleosome turnover dynamics at single-base-pair resolution. With heat shock, low-salt-soluble chromatin and stalled Pol II levels were found to decrease within gene bodies, but no overall changes were detected at transcriptional start sites. Strikingly, nucleosome turnover decreased genome-wide within gene bodies upon heat shock in a pattern similar to that observed with inhibition of Pol II elongation, especially at genes involved in the ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5415521 Tue, 15 Nov 2011 05:00:00 +0100 5415521 http://www.medworm.com/index.php?rid=5415520&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F22%2F2374%3Frss%3D1 CLOCK (CLK) is a master transcriptional regulator of the circadian clock in Drosophila. To identify CLK direct target genes and address circadian transcriptional regulation in Drosophila, we performed chromatin immunoprecipitation (ChIP) tiling array assays (ChIP–chip) with a number of circadian proteins. CLK binding cycles on at least 800 sites with maximal binding in the early night. The CLK partner protein CYCLE (CYC) is on most of these sites. The CLK/CYC heterodimer is joined 4–6 h later by the transcriptional repressor PERIOD (PER), indicating that the majority of CLK targets are regulated similarly to core circadian genes. About 30% of target genes also show cycling RNA polymerase II (Pol II) binding. Many of these generate cycling RNAs despite not being documented in pr... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5415520 Tue, 15 Nov 2011 05:00:00 +0100 5415520 http://www.medworm.com/index.php?rid=5415519&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F22%2F2361%3Frss%3D1 The establishment of body axes in multicellular organisms requires accurate control of microtubule polarization. Mutations in Drosophila PIWI-interacting RNA (piRNA) pathway genes often disrupt the axes of the oocyte. This results from the activation of the DNA damage checkpoint factor Checkpoint kinase 2 (Chk2) due to transposon derepression. A piRNA pathway gene, maelstrom (mael), is critical for the establishment of oocyte polarity in the developing egg chamber during Drosophila oogenesis. We show that Mael forms complexes with microtubule-organizing center (MTOC) components, including Centrosomin, Mini spindles, and Tubulin. We also show that Mael colocalizes with αTubulin and Tubulin to centrosomes in dividing cyst cells and follicle cells. MTOC components mislocalize in mael mu... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5415519 Tue, 15 Nov 2011 05:00:00 +0100 5415519 http://www.medworm.com/index.php?rid=5415518&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F22%2F2347%3Frss%3D1 The membrane of the primary cilium is a highly specialized compartment that organizes proteins to achieve spatially ordered signaling. Disrupting ciliary organization leads to diseases called ciliopathies, with phenotypes ranging from retinal degeneration and cystic kidneys to neural tube defects. How proteins are selectively transported to and organized in the primary cilium remains unclear. Using a proteomic approach, we identified the ARL3 effector UNC119 as a binding partner of the myristoylated ciliopathy protein nephrocystin-3 (NPHP3). We mapped UNC119 binding to the N-terminal 200 residues of NPHP3 and found the interaction requires myristoylation. Creating directed mutants predicted from a structural model of the UNC119–myristate complex, we identified highly conserved phenyl... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5415518 Tue, 15 Nov 2011 05:00:00 +0100 5415518 http://www.medworm.com/index.php?rid=5415517&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F22%2F2333%3Frss%3D1 The Hedgehog (Hh) pathway is essential for vertebrate embryogenesis, and excessive Hh target gene activation can cause cancer in humans. Here we show that Neuropilin 1 (Nrp1) and Nrp2, transmembrane proteins with roles in axon guidance and vascular endothelial growth factor (VEGF) signaling, are important positive regulators of Hh signal transduction. Nrps are expressed at times and locations of active Hh signal transduction during mouse development. Using cell lines lacking key Hh pathway components, we show that Nrps mediate Hh transduction between activated Smoothened (Smo) protein and the negative regulator Suppressor of Fused (SuFu). Nrp1 transcription is induced by Hh signaling, and Nrp1 overexpression increases maximal Hh target gene activation, indicating the existence of a positiv... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5415517 Tue, 15 Nov 2011 05:00:00 +0100 5415517 http://www.medworm.com/index.php?rid=5415516&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F22%2F2327%3Frss%3D1 Hox transcription factors exhibit an evolutionarily conserved functional hierarchy, termed phenotypic suppression, in which the activity of posterior Hox proteins dominates over more anterior Hox proteins. Using directly regulated Hox targeted reporter genes in Drosophila, we show that posterior Hox proteins suppress the activities of anterior ones by competing for cofactor-dependent DNA binding. Furthermore, we map a motif in the posterior Hox protein Abdominal-A (AbdA) that is required for phenotypic suppression and facilitates cooperative DNA binding with the Hox cofactor Extradenticle (Exd). Together, these results suggest that Hox-specific motifs endow posterior Hox proteins with the ability to dominate over more anterior ones via a cofactor-dependent DNA-binding mechanism. (Source: G... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5415516 Tue, 15 Nov 2011 05:00:00 +0100 5415516 http://www.medworm.com/index.php?rid=5415515&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F22%2F2321%3Frss%3D1 In this issue of Genes & Development, Abruzzi et al. (pp. 2374–2386) use chromatin immunoprecipitation (ChIP) tiling array assays (ChIP–chip) to show that physical interactions between circadian (24-h) clock machineries and genomes are more widespread than previously thought and provide novel insights into how clocks drive daily rhythms in global gene expression. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5415515 Tue, 15 Nov 2011 05:00:00 +0100 5415515 http://www.medworm.com/index.php?rid=5394449&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F21%2F2306%3Frss%3D1 We report a multifunctional gene-trapping approach, which generates full-length Citrine fusions with endogenous proteins and conditional mutants from a single integration event of the FlipTrap vector. We identified 170 FlipTrap zebrafish lines with diverse tissue-specific expression patterns and distinct subcellular localizations of fusion proteins generated by the integration of an internal citrine exon. Cre-mediated conditional mutagenesis is enabled by heterotypic lox sites that delete Citrine and "flip" in its place mCherry with a polyadenylation signal, resulting in a truncated fusion protein. Inducing recombination with Cerulean-Cre results in fusion proteins that often mislocalize, exhibit mutant phenotypes, and dramatically knock down wild-type transcript levels. FRT sites in the v... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5394449 Fri, 04 Nov 2011 04:00:00 +0100 5394449 http://www.medworm.com/index.php?rid=5394448&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F21%2F2291%3Frss%3D1 In this study, we demonstrate that Nkx2.2 is part of a large repression complex in pancreatic β cells that includes DNMT3a, Grg3, and HDAC1. Mutation of the endogenous Nkx2.2 tinman (TN) domain in mice abolishes the interaction between Nkx2.2 and Grg3 and disrupts β-cell specification. Furthermore, we demonstrate that Nkx2.2 preferentially recruits Grg3 and HDAC1 to the methylated Aristaless homeobox gene (Arx) promoter in β cells. The Nkx2.2 TN mutation results in ectopic expression of Arx in β cells, causing β-to-α-cell transdifferentiation. A corresponding β-cell-specific deletion of DNMT3a is also sufficient to cause Arx-dependent β-to-α-cell reprogramming. Notably, subsequent removal of Arx in the β cells of Nkx2.2TNmut/TNmut mutant ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5394448 Fri, 04 Nov 2011 04:00:00 +0100 5394448 http://www.medworm.com/index.php?rid=5394447&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F21%2F2278%3Frss%3D1 The mechanism of Bax/Bak-dependent mitochondrial outer membrane permeabilization (MOMP), a central apoptotic event primarily controlled by the Bcl-2 family proteins, remains not well understood. Here, we express active Bax/Bak in bacteria, the putative origin of mitochondria, and examine their functional similarities to the bacteriophage () holin. As critical effectors for bacterial lysis, holin oligomers form membrane lesions, through which endolysin, a muralytic enzyme, escapes the cytoplasm to attack the cell wall at the end of the infection cycle. We found that active Bax/Bak, but not any other Bcl-2 family protein, displays holin behavior, causing bacterial lysis by releasing endolysin in an oligomerization-dependent manner. Strikingly, replacing the holin gene with active alleles of ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5394447 Fri, 04 Nov 2011 04:00:00 +0100 5394447 http://www.medworm.com/index.php?rid=5394446&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F21%2F2266%3Frss%3D1 Tri- and dimethylations of histone H3K9 (H3K9me3/2) and H3K27 (H3K27me3/2), both situated in the "A-R-Kme-S" sequence motif, mediate transcriptional repression of distinct genomic regions. H3K9me3/2 mainly governs constitutive heterochromatin formation, while H3K27me3/2 represses key developmental genes. The mechanisms by which histone-modifying enzymes selectively regulate the methylation states of H3K9 and H3K27 are poorly understood. Here we report the crystal structures of the catalytic fragment of UTX/KDM6A, an H3K27me3/2-specific demethylase, in the free and H3 peptide-bound forms. The catalytic jumonji domain binds H3 residues 25–33, recognizing H3R26, H3A29, and H3P30 in a sequence-specific manner, in addition to H3K27me3 in the catalytic pocket. A novel zinc-binding domain, ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5394446 Fri, 04 Nov 2011 04:00:00 +0100 5394446 http://www.medworm.com/index.php?rid=5394445&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F21%2F2254%3Frss%3D1 Nucleosomal organization in and around genes may contribute substantially to transcriptional regulation. The contribution of histone modifications to genome-wide nucleosomal organization has not been systematically evaluated. In the present study, we examine the role of H2BK123 ubiquitylation, a key regulator of several histone modifications, on nucleosomal organization at promoter, genic, and transcription termination regions in Saccharomyces cerevisiae. Using high-resolution MNase chromatin immunoprecipitation and sequencing (ChIP-seq), we map nucleosome positioning and occupancy in mutants of the H2BK123 ubiquitylation pathway. We found that H2B ubiquitylation-mediated nucleosome formation and/or stability inhibits the assembly of the transcription machinery at normally quiescent promot... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5394445 Fri, 04 Nov 2011 04:00:00 +0100 5394445 http://www.medworm.com/index.php?rid=5394444&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F21%2F2248%3Frss%3D1 Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) provides a unique opportunity to derive patient-specific stem cells with potential applications in tissue replacement therapies and without the ethical concerns of human embryonic stem cells (hESCs). However, cellular senescence, which contributes to aging and restricted longevity, has been described as a barrier to the derivation of iPSCs. Here we demonstrate, using an optimized protocol, that cellular senescence is not a limit to reprogramming and that age-related cellular physiology is reversible. Thus, we show that our iPSCs generated from senescent and centenarian cells have reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, and are indistinguishable from hESCs... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5394444 Fri, 04 Nov 2011 04:00:00 +0100 5394444 http://www.medworm.com/index.php?rid=5394443&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F21%2F2242%3Frss%3D1 Monoubiquitination of H2BK123 (H2BK123ub), catalyzed by Rad6/Bre1, is a transient histone modification with roles in transcription and is essential for establishing H3K4 and H3K79 trimethylations (H3K4me3 and H3K79me3). Here, we investigated the chromatin network around H2BK123ub by examining its localization and co-occurrence with its dependent marks as well as the transcription elongation mark H3K36me3 across the genome of Saccharomyces cerevisiae. In yeast, H2BK123ub is removed by the deubiquitinases Ubp8 and Ubp10, but their genomic target regions remain to be determined. Genome-wide maps of H2BK123ub in the absence of Ubp8 and Ubp10 revealed their distinct target loci, which were genomic sites enriched for H3K4me3 and H3K79me3, respectively. We propose an extended model of the H2BK123... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5394443 Fri, 04 Nov 2011 04:00:00 +0100 5394443 http://www.medworm.com/index.php?rid=5394442&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F21%2F2227%3Frss%3D1 Transcription factors are adaptor molecules that detect regulatory sequences in the DNA and target the assembly of protein complexes that control gene expression. Yet much of the DNA in the eukaryotic cell is in nucleosomes and thereby occluded by histones, and can be further occluded by higher-order chromatin structures and repressor complexes. Indeed, genome-wide location analyses have revealed that, for all transcription factors tested, the vast majority of potential DNA-binding sites are unoccupied, demonstrating the inaccessibility of most of the nuclear DNA. This raises the question of how target sites at silent genes become bound de novo by transcription factors, thereby initiating regulatory events in chromatin. Binding cooperativity can be sufficient for many kinds of factors to s... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5394442 Fri, 04 Nov 2011 04:00:00 +0100 5394442 http://www.medworm.com/index.php?rid=5394441&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F21%2F2223%3Frss%3D1 This study demonstrates the mechanism of site-specific demethylation by UTX/KDM6A and implicates that histone demethylases use diverse methods to accomplish target specificity. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5394441 Fri, 04 Nov 2011 04:00:00 +0100 5394441 http://www.medworm.com/index.php?rid=5342095&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F20%2F2210%3Frss%3D1 Polycomb group (PcG) proteins are required for the epigenetic maintenance of developmental genes in a silent state. Proteins in the Polycomb-repressive complex 1 (PRC1) class of the PcG are conserved from flies to humans and inhibit transcription. One hypothesis for PRC1 mechanism is that it compacts chromatin, based in part on electron microscopy experiments demonstrating that Drosophila PRC1 compacts nucleosomal arrays. We show that this function is conserved between Drosophila and mouse PRC1 complexes and requires a region with an overrepresentation of basic amino acids. While the active region is found in the Posterior Sex Combs (PSC) subunit in Drosophila, it is unexpectedly found in a different PRC1 subunit, a Polycomb homolog called M33, in mice. We provide experimental support for ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5342095 Wed, 19 Oct 2011 04:00:00 +0100 5342095 http://www.medworm.com/index.php?rid=5342094&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F20%2F2198%3Frss%3D1 Murine Chd1 (chromodomain helicase DNA-binding protein 1), a chromodomain-containing chromatin remodeling protein, is necessary for embryonic stem (ES) cell pluripotency. Chd1 binds to nucleosomes trimethylated at histone 3 Lys 4 (H3K4me3) near the beginning of active genes but not to bivalent domains also containing H3K27me3. To address the mechanism of this specificity, we reproduced H3K4me3- and CHD1-stimulated gene activation in HeLa extracts. Multidimensional protein identification technology (MuDPIT) and immunoblot analyses of purified preinitiation complexes (PICs) revealed the recruitment of CHD1 to naive chromatin but enhancement on H3K4me3 chromatin. Studies in depleted extracts showed that the Mediator coactivator complex, which controls PIC assembly, is also necessary for CHD1 ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5342094 Wed, 19 Oct 2011 04:00:00 +0100 5342094 http://www.medworm.com/index.php?rid=5342093&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F20%2F2187%3Frss%3D1 Arteries, veins, and lymphatic vessels are functionally linked, and their physical interaction is tightly regulated. The lymphatic vessels communicate with the blood vessels only at the junction of the jugular and subclavian veins. Here, we characterize the embryonic lymphovenous valves controlling this vital communication and show that they are formed by the intercalation of lymphatic endothelial cells (LECs) with a subpopulation of venous endothelial cells (ECs) at the junction of the jugular and subclavian veins. We found that unlike LEC progenitors, which move out from the veins and differentiate into mature LECs, these Prox1-expressing ECs remain in the veins and do not acquire LEC features. We demonstrate that the development of this Prox1-expressing venous EC population, and therefo... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5342093 Wed, 19 Oct 2011 04:00:00 +0100 5342093 http://www.medworm.com/index.php?rid=5342092&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F20%2F2173%3Frss%3D1 This study broadens our understanding of microRNA function in hESCs and is a valuable resource for future studies in this area. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5342092 Wed, 19 Oct 2011 04:00:00 +0100 5342092 http://www.medworm.com/index.php?rid=5342091&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F20%2F2158%3Frss%3D1 In this study, we identified a 70-kDa Cyclin K (CycK) that binds Cdk12 and Cdk13 to form two different complexes (CycK/Cdk12 or CycK/Cdk13) in human cells. The CycK/Cdk12 complex regulates phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II and expression of a small subset of human genes, as revealed in expression microarrays. Depletion of CycK/Cdk12 results in decreased expression of predominantly long genes with high numbers of exons. The most prominent group of down-regulated genes are the DNA damage response genes, including the critical regulators of genomic stability: BRCA1 (breast and ovarian cancer type 1 susceptibility protein 1), ATR (ataxia telangiectasia and Rad3-related), FANCI, and FANCD2. We show that CycK/Cdk12, rather than CycK/Cdk13, is necessary for the... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5342091 Wed, 19 Oct 2011 04:00:00 +0100 5342091 http://www.medworm.com/index.php?rid=5342090&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F20%2F2147%3Frss%3D1 We report that these oncogenic ETS proteins, but not other ETS factors, enhance prostate cell migration. Genome-wide binding analysis matched this specific biological function to occupancy of a unique set of genomic sites highlighted by the presence of ETS- and AP-1-binding sequences. ETS/AP-1-binding sequences are prototypical RAS-responsive elements, but oncogenic ETS proteins activated a RAS/MAPK transcriptional program in the absence of MAPK activation. Thus, overexpression of oncogenic ETS proteins can replace RAS/MAPK pathway activation in prostate cells. The genomic description of this ETS/AP-1-regulated, RAS-responsive, gene expression program provides a resource for understanding the role of these ETS factors in both an oncogenic setting and the developmental processes where these... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5342090 Wed, 19 Oct 2011 04:00:00 +0100 5342090 http://www.medworm.com/index.php?rid=5342089&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F20%2F2137%3Frss%3D1 In malignancies, enhanced nuclear factor-B (NF-B) activity is largely viewed as an oncogenic property that also confers resistance to chemotherapy. Recently, NF-B has been postulated to participate in a senescence-associated and possibly senescence-reinforcing cytokine response, thereby suggesting a tumor-restraining role for NF-B. Using a mouse lymphoma model and analyzing transcriptome and clinical data from lymphoma patients, we show here that therapy-induced senescence presents with and depends on active NF-B signaling, whereas NF-B simultaneously promotes resistance to apoptosis. Further characterization and genetic engineering of primary mouse lymphomas according to distinct NF-B-related oncogenic networks reminiscent of diffuse large B-cell lymphoma (DLBCL) subtypes guided us to ide... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5342089 Wed, 19 Oct 2011 04:00:00 +0100 5342089 http://www.medworm.com/index.php?rid=5342088&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F20%2F2125%3Frss%3D1 Cellular senescence acts as a potent barrier to tumorigenesis and contributes to the anti-tumor activity of certain chemotherapeutic agents. Senescent cells undergo a stable cell cycle arrest controlled by RB and p53 and, in addition, display a senescence-associated secretory phenotype (SASP) involving the production of factors that reinforce the senescence arrest, alter the microenvironment, and trigger immune surveillance of the senescent cells. Through a proteomics analysis of senescent chromatin, we identified the nuclear factor-B (NF-B) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-B acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-B su... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5342088 Wed, 19 Oct 2011 04:00:00 +0100 5342088 http://www.medworm.com/index.php?rid=5342087&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F20%2F2119%3Frss%3D1 Under conditions of limited nutrients, eukaryotic cells reprogram protein expression in a way that slows growth but enhances survival. Recent data implicate stress granules, discrete cytoplasmic foci into which untranslated mRNPs are assembled during stress, in this process. In the October 1, 2011, issue of Genes & Development, Damgaard and Lykke-Andersen (p. 2057–2068) provide mechanistic insights into the regulation of a specific subset of mRNAs bearing 5'-terminal oligopyrimidine tracts (5'TOPs) by the structurally related stress granule proteins TIA-1 and TIAR. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5342087 Wed, 19 Oct 2011 04:00:00 +0100 5342087 http://www.medworm.com/index.php?rid=5291432&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F19%2F2106%3Frss%3D1 Hfq is a bacterial post-transcriptional regulator. It facilitates base-pairing between sRNA and target mRNA. Hfq mediates DsrA-dependent translational activation of rpoS mRNA at low temperatures. rpoS encodes the stationary-phase factor S, which is the central regulator in general stress response. However, structural information on Hfq–DsrA interaction is not yet available. Although Hfq is reported to hydrolyze ATP, the ATP-binding site is still unknown. Here, we report a ternary crystal complex structure of Escherichia coli Hfq bound to a major Hfq recognition region on DsrA (AU6A) together with ADP, and a crystal complex structure of Hfq bound to ADP. AU6A binds to the proximal and distal sides of two Hfq hexamers. ADP binds to a purine-selective site on the distal side and contact... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5291432 Thu, 06 Oct 2011 04:00:00 +0100 5291432 http://www.medworm.com/index.php?rid=5291431&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F19%2F2093%3Frss%3D1 Cell growth is regulated during RNA polymerase (Pol) I transcription initiation by the conserved factor Rrn3/TIF-IA in yeast/humans. Here we provide a structure–function analysis of Rrn3 based on a combination of structural biology with in vivo and in vitro functional assays. The Rrn3 crystal structure reveals a unique HEAT repeat fold and a surface serine patch. Phosphorylation of this patch represses human Pol I transcription, and a phospho-mimetic patch mutation prevents Rrn3 binding to Pol I in vitro and reduces cell growth and Pol I gene occupancy in vivo. Cross-linking indicates that Rrn3 binds Pol I between its subcomplexes, AC40/19 and A14/43, which faces the serine patch. The corresponding region of Pol II binds the Mediator head that cooperates with transcription factor (TF... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5291431 Thu, 06 Oct 2011 04:00:00 +0100 5291431 http://www.medworm.com/index.php?rid=5291430&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F19%2F2079%3Frss%3D1 Hundreds of microRNAs (miRNAs) have been discovered in metazoans and plants, and understanding of their biogenesis has advanced dramatically; however, relatively little is known about the cofactors necessary for miRNA regulation of target gene expression. In Caenorhabditis elegans, the conserved miRNA let-7 and its paralogs, including mir-84, control the timing of stage-specific developmental events. To identify factors required for the activity of mir-84 and possibly other miRNAs, we screened for mutations that suppress the developmental defects caused by overexpression of mir-84. Mutations in the somi-1 gene prevent these defects without affecting the expression level of mir-84. Loss of somi-1 also causes phenotypes similar to deletion of mir-84, showing that somi-1 is necessary for the ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5291430 Thu, 06 Oct 2011 04:00:00 +0100 5291430 http://www.medworm.com/index.php?rid=5291429&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F19%2F2069%3Frss%3D1 The biological response to tumor necrosis factor (TNF) involves activation of MAP kinases. Here we report a mechanism of MAP kinase activation by TNF that is mediated by the Rho GTPase family members Rac/Cdc42. This signaling pathway requires Src-dependent activation of the guanosine nucleotide exchange factor Vav, activation of Rac/Cdc42, and the engagement of the Rac/Cdc42 interaction site (CRIB motif) on mixed-lineage protein kinases (MLKs). We show that this pathway is essential for full MAP kinase activation during the response to TNF. Moreover, this MLK pathway contributes to inflammation in vivo. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5291429 Thu, 06 Oct 2011 04:00:00 +0100 5291429 http://www.medworm.com/index.php?rid=5291428&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F19%2F2057%3Frss%3D1 The response of cells to changes in their environment often requires coregulation of gene networks, but little is known about how this can occur at the post-transcriptional level. An important example of post-transcriptional coregulation is the selective translational regulation in response to growth conditions of mammalian mRNAs that encode protein biosynthesis factors and contain hallmark 5'-terminal oligopyrimidine tracts (5'TOP). However, the responsible trans-factors and the mechanism by which they coregulate 5'TOP mRNAs have remained elusive. Here we identify stress granule-associated TIA-1 and TIAR proteins as key factors in human 5'TOP mRNA regulation, which upon amino acid starvation assemble onto the 5' end of 5'TOP mRNAs and arrest translation at the initiation step, as evidence... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5291428 Thu, 06 Oct 2011 04:00:00 +0100 5291428 http://www.medworm.com/index.php?rid=5291427&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F19%2F2041%3Frss%3D1 Transcriptional R loops are anomalous RNA:DNA hybrids that have been detected in organisms from bacteria to humans. These structures have been shown in eukaryotes to result in DNA damage and rearrangements; however, the mechanisms underlying these effects have remained largely unknown. To investigate this, we first show that R-loop formation induces chromosomal DNA rearrangements and recombination in Escherichia coli, just as it does in eukaryotes. More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stability. Strikingly, we found that attenuation of replication strongly suppresses R-loop-mediated DNA rearrangements in both E. coli and HeLa cells. Our findings thus provide a direct demo... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5291427 Thu, 06 Oct 2011 04:00:00 +0100 5291427 http://www.medworm.com/index.php?rid=5291426&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F19%2F2031%3Frss%3D1 DNA-dependent protein kinase (DNA-PK) is a central regulator of DNA double-strand break (DSB) repair; however, the identity of relevant DNA-PK substrates has remained elusive. NR4A nuclear orphan receptors function as sequence-specific DNA-binding transcription factors that participate in adaptive and stress-related cell responses. We show here that NR4A proteins interact with the DNA-PK catalytic subunit and, upon exposure to DNA damage, translocate to DSB foci by a mechanism requiring the activity of poly(ADP-ribose) polymerase-1 (PARP-1). At DNA repair foci, NR4A is phosphorylated by DNA-PK and promotes DSB repair. Notably, NR4A transcriptional activity is entirely dispensable in this function, and core components of the DNA repair machinery are not transcriptionally regulated by NR4A. ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5291426 Thu, 06 Oct 2011 04:00:00 +0100 5291426 http://www.medworm.com/index.php?rid=5291425&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F19%2F2025%3Frss%3D1 WUSCHEL (WUS) is a homeodomain transcription factor produced in cells of the niche/organizing center (OC) of shoot apical meristems. WUS specifies stem cell fate and also restricts its own levels by activating a negative regulator, CLAVATA3 (CLV3), in adjacent cells of the central zone (CZ). Here we show that the WUS protein, after being synthesized in cells of the OC, migrates into the CZ, where it activates CLV3 transcription by binding to its promoter elements. Using a computational model, we show that maintenance of the WUS gradient is essential to regulate stem cell number. Migration of a stem cell-inducing transcription factor into adjacent cells to activate a negative regulator, thereby restricting its own accumulation, is a theme that is unique to plant stem cell niches. (Source: G... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5291425 Thu, 06 Oct 2011 04:00:00 +0100 5291425 http://www.medworm.com/index.php?rid=5291424&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F19%2F2011%3Frss%3D1 The greatest difference between species is size; however, the developmental mechanisms determining organism growth remain poorly understood. Primordial dwarfism is a group of human single-gene disorders with extreme global growth failure (which includes Seckel syndrome, microcephalic osteodysplastic primordial dwarfism I [MOPD] types I and II, and Meier-Gorlin syndrome). Ten genes have now been identified for microcephalic primordial dwarfism, encoding proteins involved in fundamental cellular processes including genome replication (ORC1 [origin recognition complex 1], ORC4, ORC6, CDT1, and CDC6), DNA damage response (ATR [ataxia-telangiectasia and Rad3-related]), mRNA splicing (U4atac), and centrosome function (CEP152, PCNT, and CPAP). Here, we review the cellular and developmental mechan... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5291424 Thu, 06 Oct 2011 04:00:00 +0100 5291424 http://www.medworm.com/index.php?rid=5291423&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F19%2F1999%3Frss%3D1 Macroautophagy (referred to hereafter as autophagy) is a highly regulated cellular process that serves to remove damaged proteins and organelles from the cell. Autophagy contributes to an array of normal and pathological processes, and has recently emerged as a key regulator of multiple aspects of cancer biology. The role of autophagy in cancer is complex and is likely dependent on tumor type, stage, and genetic context. This complexity is illustrated by the identification of settings where autophagy acts potently to either promote or inhibit tumorigenesis. In this review, I discuss the underlying basis for these opposing functions and propose a model suggesting a dynamic role for autophagy in malignancy. Collectively, the data point to autophagy as serving as a barrier to limit tumor init... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5291423 Thu, 06 Oct 2011 04:00:00 +0100 5291423 http://www.medworm.com/index.php?rid=5244699&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F18%2F1997%3Frss%3D1 (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5244699 Wed, 21 Sep 2011 04:00:00 +0100 5244699 http://www.medworm.com/index.php?rid=5244698&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F18%2F1982%3Frss%3D1 Members of the Flamingo cadherin family are required in a number of different in vivo contexts of neural development. Even so, molecular identities downstream from the family have been poorly understood. Here we show that a LIM domain protein, Espinas (Esn), binds to an intracellular juxtamembrane domain of Flamingo (Fmi), and that this Fmi–Esn interplay elicits repulsion between dendritic branches of Drosophila sensory neurons. In wild-type larvae, branches of the same class IV dendritic arborization neuron achieve efficient coverage of its two-dimensional receptive field with minimum overlap with each other. However, this self-avoidance was disrupted in a fmi hypomorphic mutant, in an esn knockout homozygote, and in the fmi/esn trans-heterozygote. A functional fusion protein, Fmi:3... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5244698 Wed, 21 Sep 2011 04:00:00 +0100 5244698 http://www.medworm.com/index.php?rid=5244697&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F18%2F1968%3Frss%3D1 Suppression of glycogen synthase kinase 3 (GSK3) activity in neurons yields pleiotropic outcomes, causing both axon growth promotion and inhibition. Previous studies have suggested that specific GSK3 substrates, such as adenomatous polyposis coli (APC) and collapsin response mediator protein 2 (CRMP2), support axon growth by regulating the stability of axonal microtubules (MTs), but the substrate(s) and mechanisms conveying axon growth inhibition remain elusive. Here we show that CLIP (cytoplasmic linker protein)-associated protein (CLASP), originally identified as a MT plus end-binding protein, displays both plus end-binding and lattice-binding activities in nerve growth cones, and reveal that the two MT-binding activities regulate axon growth in an opposing manner: The lattice-binding ac... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5244697 Wed, 21 Sep 2011 04:00:00 +0100 5244697 http://www.medworm.com/index.php?rid=5244696&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F18%2F1955%3Frss%3D1 CUP is an eIF4E-binding protein (4E-BP) that represses the expression of specific maternal mRNAs prior to their posterior localization. Here, we show that CUP employs multiple mechanisms to repress the expression of target mRNAs. In addition to inducing translational repression, CUP maintains mRNA targets in a repressed state by promoting their deadenylation and protects deadenylated mRNAs from further degradation. Translational repression and deadenylation are independent of eIF4E binding and require both the middle and C-terminal regions of CUP, which collectively we termed the effector domain. This domain associates with the deadenylase complex CAF1–CCR4–NOT and decapping activators. Accordingly, in isolation, the effector domain is a potent trigger of mRNA degradation and p... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5244696 Wed, 21 Sep 2011 04:00:00 +0100 5244696 http://www.medworm.com/index.php?rid=5244695&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F18%2F1943%3Frss%3D1 In budding yeast, a Ras-like GTPase signaling cascade known as the mitotic exit network (MEN) promotes exit from mitosis. To ensure the accurate execution of mitosis, MEN activity is coordinated with other cellular events and restricted to anaphase. The MEN GTPase Tem1 has been assumed to be the central switch in MEN regulation. We show here that during an unperturbed cell cycle, restricting MEN activity to anaphase can occur in a Tem1 GTPase-independent manner. We found that the anaphase-specific activation of the MEN in the absence of Tem1 is controlled by the Polo kinase Cdc5. We further show that both Tem1 and Cdc5 are required to recruit the MEN kinase Cdc15 to spindle pole bodies, which is both necessary and sufficient to induce MEN signaling. Thus, Cdc15 functions as a coincidence d... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5244695 Wed, 21 Sep 2011 04:00:00 +0100 5244695 http://www.medworm.com/index.php?rid=5244694&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F18%2F1928%3Frss%3D1 Although self-renewal is the central property of stem cells, the underlying mechanism remains inadequately defined. Using a hematopoietic stem and progenitor cell (HSPC)-specific conditional induction line, we generated a compound genetic model bearing both Pten deletion and β-catenin activation. These double mutant mice exhibit a novel phenotype, including expansion of phenotypic long-term hematopoietic stem cells (LT-HSCs) without extensive differentiation. Unexpectedly, constitutive activation of β-catenin alone results in apoptosis of HSCs. However, together, the Wnt/β-catenin and PTEN/PI3k/Akt pathways interact to drive phenotypic LT-HSC expansion by inducing proliferation while simultaneously inhibiting apoptosis and blocking differentiation, demonstrating the necessit... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5244694 Wed, 21 Sep 2011 04:00:00 +0100 5244694 http://www.medworm.com/index.php?rid=5244693&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F18%2F1915%3Frss%3D1 Large intergenic noncoding RNAs (lincRNAs) are emerging as key regulators of diverse cellular processes. Determining the function of individual lincRNAs remains a challenge. Recent advances in RNA sequencing (RNA-seq) and computational methods allow for an unprecedented analysis of such transcripts. Here, we present an integrative approach to define a reference catalog of >8000 human lincRNAs. Our catalog unifies previously existing annotation sources with transcripts we assembled from RNA-seq data collected from ~4 billion RNA-seq reads across 24 tissues and cell types. We characterize each lincRNA by a panorama of >30 properties, including sequence, structural, transcriptional, and orthology features. We found that lincRNA expression is strikingly tissue-specific compared with codi... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5244693 Wed, 21 Sep 2011 04:00:00 +0100 5244693 http://www.medworm.com/index.php?rid=5244692&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F18%2F1909%3Frss%3D1 Autosomal recessive primary microcephaly (MCPH) is a neural developmental disorder in which patients display significantly reduced brain size. Mutations in Abnormal Spindle Microcephaly (ASPM) are the most common cause of MCPH. Here, we investigate the underlying functions of Aspm in brain development and find that Aspm expression is critical for proper neurogenesis and neuronal migration. The Wnt signaling pathway is known for its roles in embryogenesis, and genome-wide siRNA screens indicate that ASPM is a positive regulator of Wnt signaling. We demonstrate that knockdown of Aspm results in decreased Wnt-mediated transcription, and that expression of stabilized β-catenin can rescue this deficit. Finally, coexpression of stabilized β-catenin can rescue defects observed upon in v... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5244692 Wed, 21 Sep 2011 04:00:00 +0100 5244692 http://www.medworm.com/index.php?rid=5244691&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F18%2F1895%3Frss%3D1 AMP-activated protein kinase (AMPK) is a sensor of energy status that maintains cellular energy homeostasis. It arose very early during eukaryotic evolution, and its ancestral role may have been in the response to starvation. Recent work shows that the kinase is activated by increases not only in AMP, but also in ADP. Although best known for its effects on metabolism, AMPK has many other functions, including regulation of mitochondrial biogenesis and disposal, autophagy, cell polarity, and cell growth and proliferation. Both tumor cells and viruses establish mechanisms to down-regulate AMPK, allowing them to escape its restraining influences on growth. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5244691 Wed, 21 Sep 2011 04:00:00 +0100 5244691 http://www.medworm.com/index.php?rid=5244690&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F18%2F1881%3Frss%3D1 Analyses of small RNA expression profiles have revealed that several DNA viruses—including particularly, herpesviruses—express high levels of multiple viral microRNAs (miRNAs) in infected cells. Here, I review our current understanding of how viral miRNAs influence viral replication and pathogenesis and discuss how viruses reshape the pattern of cellular miRNA expression. Indeed, viruses are now known to both activate and repress the expression of specific cellular miRNAs, and disrupting this process can perturb the ability of viruses to replicate normally. In addition, it is now clear that virally encoded miRNAs play a key role in inhibiting antiviral innate immune responses and can also promote cell transformation in culture. While our understanding of how viruses interact wi... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5244690 Wed, 21 Sep 2011 04:00:00 +0100 5244690 http://www.medworm.com/index.php?rid=5202109&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F17%2F1871%3Frss%3D1 The fate of pluripotent cells in early mouse embryos is controlled by graded Nodal signals that are activated by the endoproteases Furin and Pace4. Soluble forms of Furin and Pace4 cleave proNodal in vitro and after secretion in transfected cells, but direct evidence for paracrine activity in vivo is elusive. Here, we show that Furin and Pace4 are released by the extraembryonic microenvironment, and that they cleave a membrane-bound reporter substrate in adjacent epiblast cells and activate Nodal to maintain pluripotency. Secreted Pace4 and Furin also stimulated mesoderm formation, whereas endoderm was only induced by Pace4, correlating with a difference in the spatiotemporal distribution of these proteolytic activities. Our analysis of paracrine Furin and Pace4 activities and their in viv... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5202109 Tue, 06 Sep 2011 04:00:00 +0100 5202109 http://www.medworm.com/index.php?rid=5202108&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F17%2F1859%3Frss%3D1 One of the major DNA interstrand cross-link (ICL) repair pathways in mammalian cells is coupled to replication, but the mechanistic roles of the critical factors involved remain largely elusive. Here, we show that purified human SNM1A (hSNM1A), which exhibits a 5'–3' exonuclease activity, can load from a single DNA nick and digest past an ICL on its substrate strand. hSNM1A-depleted cells are ICL-sensitive and accumulate replication-associated DNA double-strand breaks (DSBs), akin to ERCC1-depleted cells. These DSBs are Mus81-induced, indicating that replication fork cleavage by Mus81 results from the failure of the hSNM1A- and XPF–ERCC1-dependent ICL repair pathway. Our results reveal how collaboration between hSNM1A and XPF–ERCC1 is necessary to initiate ICL repair in r... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5202108 Tue, 06 Sep 2011 04:00:00 +0100 5202108 http://www.medworm.com/index.php?rid=5202107&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F17%2F1847%3Frss%3D1 The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that th... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5202107 Tue, 06 Sep 2011 04:00:00 +0100 5202107 http://www.medworm.com/index.php?rid=5202106&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F17%2F1835%3Frss%3D1 The silent information regulator 2/3/4 (Sir2/3/4) complex is required for gene silencing at the silent mating-type loci and at telomeres in Saccharomyces cerevisiae. Sir3 is closely related to the origin recognition complex 1 subunit and consists of an N-terminal bromo-adjacent homology (BAH) domain and a C-terminal AAA+ ATPase-like domain. Here, through a combination of structure biology and exhaustive mutagenesis, we identified unusual, silencing-specific features of the AAA+ domain of Sir3. Structural analysis of the putative nucleotide-binding pocket in this domain reveals a shallow groove that would preclude nucleotide binding. Mutation of this site has little effect on Sir3 function in vivo. In contrast, several surface regions are shown to be necessary for the Sir3 silencing functio... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5202106 Tue, 06 Sep 2011 04:00:00 +0100 5202106 http://www.medworm.com/index.php?rid=5202105&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F17%2F1820%3Frss%3D1 The E2F family of transcription factors regulates the expression of both genes associated with cell proliferation and genes that regulate cell death. The net outcome is dependent on cellular context and tissue environment. The mir-11 gene is located in the last intron of the Drosophila E2F1 homolog gene dE2f1, and its expression parallels that of dE2f1. Here, we investigated the role of miR-11 and found that miR-11 specifically modulated the proapoptotic function of its host gene, dE2f1. A mir-11 mutant was highly sensitive to dE2F1-dependent, DNA damage-induced apoptosis. Consistently, coexpression of miR-11 in transgenic animals suppressed dE2F1-induced apoptosis in multiple tissues, while exerting no effect on dE2F1-driven cell proliferation. Importantly, miR-11 repressed the expression... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5202105 Tue, 06 Sep 2011 04:00:00 +0100 5202105 http://www.medworm.com/index.php?rid=5202104&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F17%2F1807%3Frss%3D1 Human telomere function is mediated by shelterin, a six-subunit complex that is required for telomere replication, protection, and cohesion. TIN2, the central component of shelterin, has binding sites to three subunits: TRF1, TRF2, and TPP1. Here we identify a fourth partner, heterochromatin protein 1 (HP1), that binds to a conserved canonical HP1-binding motif, PXVXL, in the C-terminal domain of TIN2. We show that HP1 localizes to telomeres in S phase, where it is required to establish/maintain cohesion. We further demonstrate that the HP1-binding site in TIN2 is required for sister telomere cohesion and can impact telomere length maintenance by telomerase. Remarkably, the PTVML HP1-binding site is embedded in the recently identified cluster of mutations in TIN2 that gives rise to dyskera... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5202104 Tue, 06 Sep 2011 04:00:00 +0100 5202104 http://www.medworm.com/index.php?rid=5202103&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F17%2F1796%3Frss%3D1 Living organisms, from bacteria to humans, display a coordinated transcriptional response to xenobiotic exposure, inducing enzymes and transporters that facilitate detoxification. Several transcription factors have been identified in vertebrates that contribute to this regulatory response. In contrast, little is known about this pathway in insects. Here we show that the Drosophila Nrf2 (NF-E2-related factor 2) ortholog CncC (cap ‘n’ collar isoform-C) is a central regulator of xenobiotic detoxification responses. A binding site for CncC and its heterodimer partner Maf (muscle aponeurosis fibromatosis) is sufficient and necessary for robust transcriptional responses to three xenobiotic compounds: phenobarbital (PB), chlorpromazine, and caffeine. Genetic manipulations that alter t... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5202103 Tue, 06 Sep 2011 04:00:00 +0100 5202103 http://www.medworm.com/index.php?rid=5202102&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F17%2F1783%3Frss%3D1 Axial patterning of the embryonic brain requires a precise balance between canonical Wnt signaling, which dorsalizes the nervous system, and Sonic hedgehog (Shh), which ventralizes it. The ventral anterior homeobox (Vax) transcription factors are induced by Shh and ventralize the forebrain through a mechanism that is poorly understood. We therefore sought to delineate direct Vax target genes. Among these, we identify an extraordinarily conserved intronic region within the gene encoding Tcf7l2, a key mediator of canonical Wnt signaling. This region functions as a Vax2-activated internal promoter that drives the expression of dnTcf7l2, a truncated Tcf7l2 isoform that cannot bind β-catenin and that therefore acts as a potent dominant-negative Wnt antagonist. Vax2 concomitantly activates ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5202102 Tue, 06 Sep 2011 04:00:00 +0100 5202102 http://www.medworm.com/index.php?rid=5202101&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F17%2F1770%3Frss%3D1 Polyadenylation [poly(A)] signals (PAS) are a defining feature of eukaryotic protein-coding genes. The central sequence motif AAUAAA was identified in the mid-1970s and subsequently shown to require flanking, auxiliary elements for both 3'-end cleavage and polyadenylation of premessenger RNA (pre-mRNA) as well as to promote downstream transcriptional termination. More recent genomic analysis has established the generality of the PAS for eukaryotic mRNA. Evidence for the mechanism of mRNA 3'-end formation is outlined, as is the way this RNA processing reaction communicates with RNA polymerase II to terminate transcription. The widespread phenomenon of alternative poly(A) site usage and how this interrelates with pre-mRNA splicing is then reviewed. This shows that gene expression can be dras... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5202101 Tue, 06 Sep 2011 04:00:00 +0100 5202101 http://www.medworm.com/index.php?rid=5202100&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F17%2F1763%3Frss%3D1 In this issue of Genes & Development, Yang and colleagues (pp. 1847–1858) identify new components of a small ubiquitin-like modifier (SUMO)-like interaction network that orchestrates and fine-tunes the Fanconi anemia (FA) pathway and replication-coupled repair. This new pathway emphasizes the intricate interplay of ubiquitin (Ub) and SUMO networks in the DNA damage response. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5202100 Tue, 06 Sep 2011 04:00:00 +0100 5202100 http://www.medworm.com/index.php?rid=5202099&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F17%2F1759%3Frss%3D1 In canonical Wnt signaling, β-catenin translocates to the cell nucleus, interacting with Tcf/Lef factors to activate transcription of Wnt target genes. In this issue of Genes & Development, Vacik and colleagues (pp. 1783–1795) report that a highly conserved sequence in intron 5 of Tcf7l2 conceals an internal promoter region that, when activated by Vax2, drives transcription of truncated Tcf7l2 mRNAs. The encoded Tcf7l2 protein binds to DNA, but not β-catenin, and therefore acts as a dominant-negative Wnt antagonist. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5202099 Tue, 06 Sep 2011 04:00:00 +0100 5202099 http://www.medworm.com/index.php?rid=5153354&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F16%2F1746%3Frss%3D1 MdmX, also known as Mdm4, is a critical negative regulator of p53, and its overexpression serves to block p53 tumor suppressor function in many cancers. Consequently, inhibiting MdmX has emerged as an attractive approach to restoring p53 function in those cancers that retain functional p53. However, the consequences of acute systemic MdmX inhibition in normal adult tissues remain unknown. To determine directly the effects of systemic MdmX inhibition in normal tissues and in tumors, we crossed mdmX–/– mice into the p53ERTAM knockin background. In place of wild-type p53, p53ERTAM knockin mice express a variant of p53, p53ERTAM, that is completely dependent on 4-hydroxy-tamoxifen for its activity. MdmX inhibition was then modeled by restoring p53 function in these MdmX-deficient m... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5153354 Wed, 17 Aug 2011 23:00:00 +0100 5153354 http://www.medworm.com/index.php?rid=5153353&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F16%2F1734%3Frss%3D1 The miR-17~92 cluster is a potent microRNA-encoding oncogene. Here, we show that miR-17~92 synergizes with loss of Rb family members to promote retinoblastoma. We observed miR-17~92 genomic amplifications in murine retinoblastoma and high expression of miR-17~92 in human retinoblastoma. While miR-17~92 was dispensable for mouse retinal development, miR-17~92 overexpression, together with deletion of Rb and p107, led to rapid emergence of retinoblastoma with frequent metastasis to the brain. miR-17~92 oncogenic function in retinoblastoma was not mediated by a miR-19/PTEN axis toward apoptosis suppression, as found in lymphoma/leukemia models. Instead, miR-17~92 increased the proliferative capacity of Rb/p107-deficient retinal cells. We found that deletion of Rb family members led to compens... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5153353 Wed, 17 Aug 2011 23:00:00 +0100 5153353 http://www.medworm.com/index.php?rid=5153352&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F16%2F1716%3Frss%3D1 Loss of extracellular matrix (ECM) attachment leads to metabolic impairments that limit cellular energy production. Characterization of the metabolic alterations induced by ECM detachment revealed a dramatic decrease in uptake of glucose, glutamine, and pyruvate, and a consequent decrease in flux through glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle. However, flux through pyruvate dehydrogenase (PDH) is disproportionally decreased, concomitant with increased expression of the PDH inhibitory kinase, PDH kinase 4 (PDK4), and increased carbon secretion. Overexpression of ErbB2 maintains PDH flux by suppressing PDK4 expression in an Erk-dependent manner, and Erk signaling also regulates PDH flux in ECM-attached cells. Additionally, epidermal growth factor (E... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5153352 Wed, 17 Aug 2011 23:00:00 +0100 5153352 http://www.medworm.com/index.php?rid=5153351&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F16%2F1702%3Frss%3D1 The noncoding Tsix RNA is an antisense repressor of Xist and regulates X inactivation in mice. Tsix is essential for preventing the inactivation of the maternally inherited X chromosome in extraembryonic lineages where imprinted X-chromosome inactivation (XCI) occurs. Here we establish an inducible Tsix expression system for investigating Tsix function in development. We show that Tsix has a clear functional window in extraembryonic development. Within this window, Tsix can repress Xist, which is accompanied by DNA methylation of the Xist promoter. As a consequence of Xist repression, reactivation of the inactive X chromosome (Xi) is widely observed. In the parietal endoderm, Tsix represses Xist and causes reactivation of an Xi-linked GFP transgene throughout development, whereas Tsix prog... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5153351 Wed, 17 Aug 2011 23:00:00 +0100 5153351 http://www.medworm.com/index.php?rid=5153350&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F16%2F1686%3Frss%3D1 A major role of the RNAi pathway in Schizosaccharomyces pombe is to nucleate heterochromatin, but it remains unclear whether this mechanism is conserved. To address this question in Drosophila, we performed genome-wide localization of Argonaute2 (AGO2) by chromatin immunoprecipitation (ChIP)-seq in two different embryonic cell lines and found that AGO2 localizes to euchromatin but not heterochromatin. This localization pattern is further supported by immunofluorescence staining of polytene chromosomes and cell lines, and these studies also indicate that a substantial fraction of AGO2 resides in the nucleus. Intriguingly, AGO2 colocalizes extensively with CTCF/CP190 chromatin insulators but not with genomic regions corresponding to endogenous siRNA production. Moreover, AGO2, but not its ca... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5153350 Wed, 17 Aug 2011 23:00:00 +0100 5153350 http://www.medworm.com/index.php?rid=5153349&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F16%2F1680%3Frss%3D1 Using single transcription factors to reprogram cells could produce important insights into the epigenetic mechanisms that direct normal differentiation, or counter inappropriate plasticity, or even provide new ways of manipulating normal ontogeny in vitro to control lineage diversification and differentiation. We enforced Pdx1 expression from the Neurogenin-3-expressing endocrine commitment point onward and found during the embryonic period a minor increased β-cell allocation with accompanying reduced α-cell numbers. More surprisingly, almost all remaining Pdx1-containing glucagon/Arx-producing cells underwent a fairly rapid conversion at postnatal stages, through glucagon–insulin double positivity, to a state indistinguishable from normal β cells, resulting in compl... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5153349 Wed, 17 Aug 2011 23:00:00 +0100 5153349 http://www.medworm.com/index.php?rid=5153348&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F16%2F1674%3Frss%3D1 We have determined the cistrome and transcriptome for the nuclear receptor liver receptor homolog-1 (LRH-1) in exocrine pancreas. Chromatin immunoprecipitation (ChIP)-seq and RNA-seq analyses reveal that LRH-1 directly induces expression of genes encoding digestive enzymes and secretory and mitochondrial proteins. LRH-1 cooperates with the pancreas transcription factor 1-L complex (PTF1-L) in regulating exocrine pancreas-specific gene expression. Elimination of LRH-1 in adult mice reduced the concentration of several lipases and proteases in pancreatic fluid and impaired pancreatic fluid secretion in response to cholecystokinin. Thus, LRH-1 is a key regulator of the exocrine pancreas-specific transcriptional network required for the production and secretion of pancreatic fluid. (Source: Ge... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5153348 Wed, 17 Aug 2011 23:00:00 +0100 5153348 http://www.medworm.com/index.php?rid=5153347&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F16%2F1668%3Frss%3D1 The target of rapamycin (TOR) complex 1 (TORC1) is a central cell growth regulator in response to a wide array of signals. The Rag GTPases play an essential role in relaying amino acid signals to TORC1 activation through direct interaction with raptor and recruitment of the TORC1 complex to lysosomes. Here we present the crystal structure of the Gtr1p–Gtr2p complex, the Rag homologs from Saccharomyces cerevisiae, at 2.8 Å resolution. The heterodimeric GTPases reveal a pseudo-twofold symmetric organization. Structure-guided functional analyses of RagA–RagC, the human homologs of Gtr1p–Gtr2p, show that both G domains (N-terminal GTPase domains) and dimerization are important for raptor binding. In particular, the switch regions of the G domain in RagA are indispensibl... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5153347 Wed, 17 Aug 2011 23:00:00 +0100 5153347 http://www.medworm.com/index.php?rid=5153346&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F16%2F1663%3Frss%3D1 Retinoblastoma is a rare pediatric cancer that has served as a paradigm to investigate the mechanisms of tumorigenesis. In this issue of Genes & Development, Conkrite and colleagues (pp. 1734–1745) found high levels of the miR-17~92 and miR-106b-25 microRNAs in primary retinoblastomas and show that overexpression of miR-17~92 accelerates retinoblastoma development in mice by promoting proliferation, in part by reducing expression of the cell cycle inhibitor p21. These experiments identify the RB/miR-17~92/p21 axis as a critical regulator of retinoblastoma tumorigenesis and potentially many other cancers. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5153346 Wed, 17 Aug 2011 23:00:00 +0100 5153346 http://www.medworm.com/index.php?rid=5115546&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1662%3Frss%3D1 (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115546 Mon, 08 Aug 2011 23:00:00 +0100 5115546 http://www.medworm.com/index.php?rid=5115545&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1654%3Frss%3D1 Nodal signaling, mediated through SMAD transcription factors, is necessary for pluripotency maintenance and endoderm commitment. We identified a new motif, termed SMAD complex-associated (SCA), that is bound by SMAD2/3/4 and FOXH1 in human embryonic stem cells (hESCs) and derived endoderm. We demonstrate that two basic helix–loop–helix (bHLH) proteins—HEB and E2A—bind the SCA motif at regions overlapping SMAD2/3 and FOXH1. Furthermore, we show that HEB and E2A associate with SMAD2/3 and FOXH1, suggesting they form a complex at critical target regions. This association is biologically important, as E2A is critical for mesendoderm specification, gastrulation, and Nodal signal transduction in Xenopus tropicalis embryos. Taken together, E proteins are novel Nodal signal... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115545 Mon, 08 Aug 2011 23:00:00 +0100 5115545 http://www.medworm.com/index.php?rid=5115544&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1641%3Frss%3D1 Human mammary glands arise from multipotent progenitor cells, which likely respond both to cell-autonomous and to extrinsic cues. However, the identity of these cues and how they might act remain unclear. We analyzed HER1 ligand effects on mammary morphogenesis using a three-dimensional organoid model generated from human breast tissue that recapitulates both qualitatively and quantitatively the normal ductal network in situ. Strikingly, different HER1 ligands generate distinct patterns of cell fate. Epidermal growth factor (EGF) causes a massive expansion of the myoepithelial lineage. Amphiregulin, in contrast, enables normal ductal development. These differences cannot be ascribed to preferential apoptosis or proliferation of differentiated cell populations, but are dependent on HER1 sig... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115544 Mon, 08 Aug 2011 23:00:00 +0100 5115544 http://www.medworm.com/index.php?rid=5115543&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1628%3Frss%3D1 Although human cancers have complex genotypes and are genomically unstable, they often remain dependent on the continued presence of single-driver mutations—a phenomenon dubbed "oncogene addiction." Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets. Here, we implement an integrative approach that combines genetically defined mouse models, transcriptional profiling, and a novel inducible RNAi platform to characterize cellular programs that underlie addiction to MLL-AF9—a fusion oncoprotein involved in aggressive forms of acute myeloid leukemia (AML). We show tha... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115543 Mon, 08 Aug 2011 23:00:00 +0100 5115543 http://www.medworm.com/index.php?rid=5115542&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1613%3Frss%3D1 A key question concerns the mechanisms that determine temporal identity in stem cells. Fetal hematopoietic stem cells (HSCs) differ from adult HSCs in terms of gene expression profile, surface marker expression, differentiation, and self-renewal capacity. We previously showed that the transcription factor SOX17 is expressed by fetal, but not adult, HSCs and is required for the maintenance of fetal and neonatal, but not adult, HSCs. In the current study, we show that ectopic expression of Sox17 in adult HSCs and transiently reconstituting multipotent progenitors was sufficient to confer increased self-renewal potential and the expression of fetal HSC genes, including fetal HSC surface markers. Sox17 expression enabled transiently reconstituting adult progenitors to give long-term multilinea... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115542 Mon, 08 Aug 2011 23:00:00 +0100 5115542 http://www.medworm.com/index.php?rid=5115541&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1601%3Frss%3D1 Little is known about how particle-specific proteins are assembled on spliceosomal small nuclear ribonucleoproteins (snRNPs). Brr2p is a U5 snRNP-specific RNA helicase required for spliceosome catalytic activation and disassembly. In yeast, the Aar2 protein is part of a cytoplasmic precursor U5 snRNP that lacks Brr2p and is replaced by Brr2p in the nucleus. Here we show that Aar2p and Brr2p bind to different domains in the C-terminal region of Prp8p; Aar2p interacts with the RNaseH domain, whereas Brr2p interacts with the Jab1/MPN domain. These domains are connected by a long, flexible linker, but the Aar2p–RNaseH complex sequesters the Jab1/MPN domain, thereby preventing binding by Brr2p. Aar2p is phosphorylated in vivo, and a phospho-mimetic S253E mutation in Aar2p leads to disrupt... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115541 Mon, 08 Aug 2011 23:00:00 +0100 5115541 http://www.medworm.com/index.php?rid=5115540&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1595%3Frss%3D1 Subependymal nodules (SENs) and subependymal giant cell astrocytomas (SEGAs) are common brain lesions found in patients with tuberous sclerosis complex (TSC). These brain lesions present a mixed glioneuronal phenotype and have been hypothesized to originate from neural stem cells. However, this hypothesis has not been tested empirically. Here, we report that loss of Tsc1 in mouse subventricular zone (SVZ) neural stem/progenitor cells (NSPCs) results in formation of SEN- and SEGA-like structural abnormalities in the lateral ventricle, the consequence of abnormal migration of NSPCs following Tsc1 loss. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115540 Mon, 08 Aug 2011 23:00:00 +0100 5115540 http://www.medworm.com/index.php?rid=5115539&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1589%3Frss%3D1 This study provides the first evidence to support the ability of intron-interrupted miRNA precursors to produce functional regulators and identifies an additional modality available for metazoan miRNA production. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115539 Mon, 08 Aug 2011 23:00:00 +0100 5115539 http://www.medworm.com/index.php?rid=5115538&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1583%3Frss%3D1 Remote distal enhancers may be located tens or thousands of kilobases away from their promoters. How they control gene expression is still poorly understood. Here, we analyze the influence of a remote enhancer on the balance between repression (Polycomb—PcG) and activation (Trithorax—TrxG) of a developmentally regulated gene associated with a CpG island. We reveal its essential, nonredundant role in clearing the PcG complex and H3K27me3 from the CpG island. In the absence of the enhancer, the H3K27me3 demethylase (JMJD3) is not recruited to the CpG island. We propose a new role of long-range regulatory elements in removing repressive PcG complexes. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115538 Mon, 08 Aug 2011 23:00:00 +0100 5115538 http://www.medworm.com/index.php?rid=5115537&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1568%3Frss%3D1 Eukaryotic cell cycle transitions are driven by E3 ubiquitin ligases that catalyze the ubiquitylation and destruction of specific protein targets. For example, the anaphase-promoting complex/cyclosome (APC/C) promotes the exit from mitosis via destruction of securin and mitotic cyclins, whereas CRL1Skp2 allows entry into S phase by targeting the destruction of the cyclin-dependent kinase (CDK) inhibitor p27. Recently, an E3 ubiquitin ligase called CRL4Cdt2 has been characterized, which couples proteolysis to DNA synthesis via an unusual mechanism that involves display of substrate degrons on the DNA polymerase processivity factor PCNA. Through its destruction of Cdt1, p21, and Set8, CRL4Cdt2 has emerged as a master regulator that prevents rereplication in S phase. In addition, it also targ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115537 Mon, 08 Aug 2011 23:00:00 +0100 5115537 http://www.medworm.com/index.php?rid=5115536&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1563%3Frss%3D1 The U5 snRNP (small ribonucleoprotein) contains several functionally crucial splicing factors that form an extensive interaction network both in the snRNP and within the spliceosome. In this issue of Genes & Development, Weber and colleagues (pp. 1601–1612) shed light on the dynamic assembly of this critical spliceosomal component and elucidate the molecular interactions underlying the ordered addition of Brr2, a pivotal spliceosomal helicase, to the U5 snRNP. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115536 Mon, 08 Aug 2011 23:00:00 +0100 5115536 http://www.medworm.com/index.php?rid=5115535&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F15%2F1557%3Frss%3D1 Maturation of hematopoietic stem cells (HSCs) from fetal to adult state and differentiation to progenitors are thought to follow a one-way street. In this issue of Genes & Development, He and colleagues (pp. 1613–1627) show that overexpression of Sox17 can convert adult multipotential progenitors to self-renewing HSCs that possess fetal properties. These findings challenge the irreversibility of hematopoietic development, and open up new perspectives to understand the different forms of HSC self-renewal at distinct stages of ontogeny and during transformation. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5115535 Mon, 08 Aug 2011 23:00:00 +0100 5115535 http://www.medworm.com/index.php?rid=5034551&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F14%2F1556%3Frss%3D1 (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5034551 Thu, 14 Jul 2011 23:00:00 +0100 5034551 http://www.medworm.com/index.php?rid=5034550&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F14%2F1544%3Frss%3D1 Stochastic processes are thought to mediate localization of membrane-associated chemotaxis signaling clusters in peritrichous bacteria. Here, we identified a new family of ParA-like ATPases (designated ParC [for partitioning chemotaxis]) encoded within chemotaxis operons of many polar-flagellated -proteobacteria that actively promote polar localization of chemotaxis proteins. In Vibrio cholerae, a single ParC focus is found at the flagellated old pole in newborn cells, and later bipolar ParC foci develop as the cell matures. The cell cycle-dependent redistribution of ParC occurs by its release from the old pole and subsequent relocalization at the new pole, consistent with a "diffusion and capture" model for ParC dynamics. Chemotaxis proteins encoded in the same cluster as ParC have a simi... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5034550 Thu, 14 Jul 2011 23:00:00 +0100 5034550 http://www.medworm.com/index.php?rid=5034549&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F14%2F1528%3Frss%3D1 The p53 pathway is critical for tumor suppression, as the majority of human cancer has a faulty p53. Here, we identified RNPC1, a p53 target and a RNA-binding protein, as a critical regulator of p53 translation. We showed that ectopic expression of RNPC1 inhibited, whereas knockdown of RNPC1 increased, p53 translation under normal and stress conditions. We also showed that RNPC1 prevented cap-binding protein eIF4E from binding p53 mRNA via its C-terminal domain for physical interaction with eIF4E, and its N-terminal domain for binding p53 mRNA. Consistent with this, we found that RNPC1 directly binds to p53 5' and 3'untranslated regions (UTRs). Importantly, we showed that RNPC1 inhibits ectopic expression of p53 in a dose-dependent manner via p53 5' or 3' UTR. Moreover, we showed that loss... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5034549 Thu, 14 Jul 2011 23:00:00 +0100 5034549 http://www.medworm.com/index.php?rid=5034548&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F14%2F1510%3Frss%3D1 Autophagy is a conserved cellular process for bulk degradation of intracellular protein and organelles in lysosomes. In contrast to elegant studies of beclin1 using mouse models and cultured cells demonstrating a tumor suppression function for autophagy, knockout of other essential autophagy proteins such as ATG5, ATG7, or FIP200 (FAK family-interacting protein of 200 kDa) in various tissues did not lead to malignant tumor development in vivo. Here, we report that inhibition of autophagy by FIP200 ablation suppresses mammary tumor initiation and progression in a mouse model of breast cancer driven by the PyMT oncogene. Deletion of FIP200 resulted in multiple autophagy defects including accumulation of ubiquitinated protein aggregates and p62/SQSTM1, deficient LC3 conversion, and increased ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5034548 Thu, 14 Jul 2011 23:00:00 +0100 5034548 http://www.medworm.com/index.php?rid=5034547&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F14%2F1499%3Frss%3D1 The Spt–Ada–Gcn5–acetyltransferase (SAGA) complex was discovered from Saccharomyces cerevisiae and has been well characterized as an important transcriptional coactivator that interacts both with sequence-specific transcription factors and the TATA-binding protein TBP. SAGA contains a histone acetyltransferase and a ubiquitin protease. In metazoans, SAGA is essential for development, yet little is known about the function of SAGA in differentiating tissue. We analyzed the composition, interacting proteins, and genomic distribution of SAGA in muscle and neuronal tissue of late stage Drosophila melanogaster embryos. The subunit composition of SAGA was the same in each tissue; however, SAGA was associated with considerably more transcription factors in muscle compared with n... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5034547 Thu, 14 Jul 2011 23:00:00 +0100 5034547 http://www.medworm.com/index.php?rid=5034546&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F14%2F1486%3Frss%3D1 In this study, we performed global genomic analyses in murine embryonic stem (ES) cells and in human cells in response to activation signals. We identified an essential role for the ELL (eleven–nineteen lysine-rich leukemia gene)/P-TEFb (positive transcription elongation factor)-containing super elongation complex (SEC) in the regulation of gene expression, including several genes bearing paused RNA polymerase II (Pol II). Paused Pol II has been proposed to be associated with loci that respond rapidly to environmental stimuli. However, our studies in ES cells also identified a requirement for SEC at genes without paused Pol II, which also respond dynamically to differentiation signals. Our findings suggest that SEC is a major class of active P-TEFb-containing complexes required for t... Genes and Development journals http://www.medworm.com/rss/comments.php?id=5034546 Thu, 14 Jul 2011 23:00:00 +0100 5034546 http://www.medworm.com/index.php?rid=5034545&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F14%2F1476%3Frss%3D1 Nitric oxide gas acts as a short-range signaling molecule in a vast array of important physiological processes, many of which include major changes in gene expression. How these genomic responses are induced, however, is poorly understood. Here, using genetic and chemical manipulations, we show that nitric oxide is produced in the Drosophila prothoracic gland, where it acts via the nuclear receptor ecdysone-induced protein 75 (E75), reversing its ability to interfere with its heterodimer partner, Drosophila hormone receptor 3 (DHR3). Manipulation of these interactions leads to gross alterations in feeding behavior, fat deposition, and developmental timing. These neuroendocrine interactions and consequences appear to be conserved in vertebrates. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5034545 Thu, 14 Jul 2011 23:00:00 +0100 5034545 http://www.medworm.com/index.php?rid=5034544&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F14%2F1470%3Frss%3D1 Small cell lung cancer (SCLC) is an aggressive cancer often diagnosed after it has metastasized. Despite the need to better understand this disease, SCLC remains poorly characterized at the molecular and genomic levels. Using a genetically engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung, we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC. We uncovered amplification of a novel, oncogenic transcription factor, Nuclear factor I/B (Nfib), in the mouse SCLC model and in human SCLC. Functional studies indicate that NFIB regulates cell viability and proliferation during transformation. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5034544 Thu, 14 Jul 2011 23:00:00 +0100 5034544 http://www.medworm.com/index.php?rid=5034543&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F14%2F1464%3Frss%3D1 To understand how chromosome shapes are determined by actions of condensins and cohesin, we devised a series of protocols in which their levels are precisely changed in Xenopus egg extracts. When the relative ratio of condensin I to II is forced to be smaller, embryonic chromosomes become shorter and thicker, being reminiscent of somatic chromosomes. Further depletion of condensin II unveils its contribution to axial shortening of chromosomes. Cohesin helps juxtapose sister chromatid arms by collaborating with condensin I and counteracting condensin II. Thus, chromosome shaping is achieved by an exquisite balance among condensin I and II and cohesin. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5034543 Thu, 14 Jul 2011 23:00:00 +0100 5034543 http://www.medworm.com/index.php?rid=5034542&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F14%2F1459%3Frss%3D1 Nitric oxide (NO) is an important second messenger involved in numerous biological processes, but how it regulates gene expression is not well understood. In this issue of Genes & Development, Cáceres and colleagues (pp. 1476–1485) report a critical requirement of NO as a direct regulator of gene expression through its binding to a heme-containing nuclear receptor in Drosophila. This may be an anciently evolved mechanism to coordinate behavior and metabolism during animal development. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5034542 Thu, 14 Jul 2011 23:00:00 +0100 5034542 http://www.medworm.com/index.php?rid=5034541&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F14%2F1453%3Frss%3D1 Peroxisome proliferator-activated receptor (PPAR) coactivator 1 α (PGC-1α) activation coordinates induction of the hepatic fasting response through coactivation of numerous transcription factors and gene programs. In the June 15, 2011, issue of Genes & Development, Lustig and colleagues (pp. 1232–1244) demonstrated that phosphorylation of PGC-1α by the p70 ribosomal protein S6 kinase 1 (S6K1) specifically interfered with the interaction between PGC-1α and HNF4α in liver and blocked the coactivation of the gluconeogenic target genes. This demonstrates how independent fine-tuning of gene programs coregulated by the same coactivator can be obtained. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=5034541 Thu, 14 Jul 2011 23:00:00 +0100 5034541 http://www.medworm.com/index.php?rid=4990334&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F13%2F1451%3Frss%3D1 (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=4990334 Thu, 30 Jun 2011 23:00:00 +0100 4990334 http://www.medworm.com/index.php?rid=4990333&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F13%2F1439%3Frss%3D1 Leaves originate from stem cells located at the shoot apical meristem. The meristem is shielded from the environment by older leaves, and leaf initiation is considered to be an autonomous process that does not depend on environmental cues. Here we show that light acts as a morphogenic signal that controls leaf initiation and stabilizes leaf positioning. Leaf initiation in tomato shoot apices ceases in the dark but resumes in the light, an effect that is mediated through the plant hormone cytokinin. Dark treatment also affects the subcellular localization of the auxin transporter PIN1 and the concomitant formation of auxin maxima. We propose that cytokinin is required for meristem propagation, and that auxin redirects cytokinin-inducible meristem growth toward organ formation. In contrast t... Genes and Development journals http://www.medworm.com/rss/comments.php?id=4990333 Thu, 30 Jun 2011 23:00:00 +0100 4990333 http://www.medworm.com/index.php?rid=4990332&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F13%2F1426%3Frss%3D1 Cell cycle regulation in hematopoietic stem cells (HSCs) is tightly controlled during homeostasis and in response to extrinsic stress. p53, a well-known tumor suppressor and transducer of diverse stress signals, has been implicated in maintaining HSC quiescence and self-renewal. However, the mechanisms that control its activity in HSCs, and how p53 activity contributes to HSC cell cycle control, are poorly understood. Here, we use a genetically engineered mouse to show that p53 C-terminal modification is critical for controlling HSC abundance during homeostasis and HSC and progenitor proliferation after irradiation. Preventing p53 C-terminal modification renders mice exquisitely radiosensitive due to defects in HSC/progenitor proliferation, a critical determinant for restoring hematopoiesi... Genes and Development journals http://www.medworm.com/rss/comments.php?id=4990332 Thu, 30 Jun 2011 23:00:00 +0100 4990332 http://www.medworm.com/index.php?rid=4990331&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F13%2F1412%3Frss%3D1 We report that although shRNAs directed against most of the PTP family were without effect, suppression of three PTPs—PRPN23, PTPRG, and PTPRR—enhanced cell motility. Furthermore, we found that suppression of PTPN23, but not PTPRG or PTPRR, induced cell invasion. Suppression of PTPN23 increased E-cadherin internalization, impaired early endosome trafficking of E-cadherin, induced the expression of mesenchymal proteins, and caused cell scattering. The activity of SRC and β-catenin was elevated when PTPN23 was suppressed. Moreover, we identified SRC, E-cadherin, and β-catenin as direct substrates of PTPN23. Inhibition of SRC with the small molecular inhibitor SU6656 blocked the effects of PTPN23 depletion. These findings suggest that loss of PTPN23 may increase the acti... Genes and Development journals http://www.medworm.com/rss/comments.php?id=4990331 Thu, 30 Jun 2011 23:00:00 +0100 4990331 http://www.medworm.com/index.php?rid=4990330&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F13%2F1399%3Frss%3D1 Blood vessel networks are typically formed by angiogenesis, a process in which new vessels form by sprouting of endothelial cells from pre-existing vessels. This process is initiated by vascular endothelial growth factor (VEGF)-mediated tip cell selection and subsequent angiogenic sprouting. Surprisingly, we found that VEGF directly controls the expression of Plexin-D1, the receptor for the traditional repulsive axon guidance cue, semaphorin 3E (Sema3E). Sema3E–Plexin-D1 signaling then negatively regulates the activity of the VEGF-induced Delta-like 4 (Dll4)–Notch signaling pathway, which controls the cell fate decision between tip and stalk cells. Using the mouse retina as a model system, we show that Plexin-D1 is selectively expressed in endothelial cells at the front of acti... Genes and Development journals http://www.medworm.com/rss/comments.php?id=4990330 Thu, 30 Jun 2011 23:00:00 +0100 4990330 http://www.medworm.com/index.php?rid=4990329&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F13%2F1384%3Frss%3D1 In metazoans, how replication origins are specified and subsequently activated is not well understood. Drosophila amplicons in follicle cells (DAFCs) are genomic regions that undergo rereplication to increase DNA copy number. We identified all DAFCs by comparative genomic hybridization, uncovering two new amplicons in addition to four known previously. The complete identification of all DAFCs enabled us to investigate these in vivo replicons with respect to parameters of transcription, localization of the origin recognition complex (ORC), and histone acetylation, yielding important insights into gene amplification as a metazoan replication model. Significantly, ORC is bound across domains spanning 10 or more kilobases at the DAFC rather than at a specific site. Additionally, ORC is bound a... Genes and Development journals http://www.medworm.com/rss/comments.php?id=4990329 Thu, 30 Jun 2011 23:00:00 +0100 4990329 http://www.medworm.com/index.php?rid=4990328&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F25%2F13%2F1371%3Frss%3D1 Three-dimensional topology of DNA in the cell nucleus provides a level of transcription regulation beyond the sequence of the linear DNA. To study the relationship between the transcriptional activity and the spatial environment of a gene, we used allele-specific chromosome conformation capture-on-chip (4C) technology to produce high-resolution topology maps of the active and inactive X chromosomes in female cells. We found that loci on the active X form multiple long-range interactions, with spatial segregation of active and inactive chromatin. On the inactive X, silenced loci lack preferred interactions, suggesting a unique random organization inside the inactive territory. However, escapees, among which is Xist, are engaged in long-range contacts with each other, enabling identification... Genes and Development journals http://www.medworm.com/rss/comments.php?id=4990328 Thu, 30 Jun 2011 23:00:00 +0100 4990328