Genes and Development
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TNF{alpha} shedding and epidermal inflammation are controlled by Jun proteins [Research Papers]
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Inducible epidermal deletion of JunB and c-Jun in adult mice causes a psoriasis-like inflammatory skin disease. Increased levels of the proinflammatory cytokine TNF play a major role in this phenotype. Here we define the underlying molecular mechanism using genetic mouse models. We show that Jun proteins control TNF shedding in the epidermis by direct transcriptional activation of tissue inhibitor of metalloproteinase-3 (TIMP-3), an inhibitor of the TNF-converting enzyme (TACE). TIMP-3 is down-regulated and TACE activity is specifically increased, leading to massive, cell-autonomous TNF shedding upon loss of both JunB and ...
Source: Genes and Development - November 16, 2009 Category: Genetics & Stem Cells Authors: Guinea-Viniegra, J., Zenz, R., Scheuch, H., Hnisz, D., Holcmann, M., Bakiri, L., Schonthaler, H. B., Sibilia, M., Wagner, E. F. Tags: Research Papers Source Type: journals
A pH-responsive riboregulator [Research Papers]Email this article to a colleague.
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The locus alx, which encodes a putative transporter, was discovered previously in a screen for genes induced under extreme alkaline conditions. Here we show that the RNA region preceding the alx ORF acts as a pH-responsive element, which, in response to high pH, leads to an increase in alx expression. Under normal growth conditions this RNA region forms a translationally inactive structure, but when exposed to high pH, a translationally active structure is formed to produce Alx. Formation of the active structure occurs while transcription is in progress under alkaline conditions and involves pausing of RNA polymerase at tw...
Source: Genes and Development - November 16, 2009 Category: Genetics & Stem Cells Authors: Nechooshtan, G., Elgrably-Weiss, M., Sheaffer, A., Westhof, E., Altuvia, S. Tags: Research Papers Source Type: journals
A novel class of small RNAs: tRNA-derived RNA fragments (tRFs) [Research Papers]Email this article to a colleague.
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New types of small RNAs distinct from microRNAs (miRNAs) are progressively being discovered in various organisms. In order to discover such novel small RNAs, a library of 17- to 26-base-long RNAs was created from prostate cancer cell lines and sequenced by ultra-high-throughput sequencing. A significant number of the sequences are derived from precise processing at the 5' or 3' end of mature or precursor tRNAs to form three series of tRFs (tRNA-derived RNA fragments): the tRF-5, tRF-3, and tRF-1 series. These sequences constitute a class of short RNAs that are second most abundant to miRNAs. Northern hybridization, quantit...
Source: Genes and Development - November 16, 2009 Category: Genetics & Stem Cells Authors: Lee, Y. S., Shibata, Y., Malhotra, A., Dutta, A. Tags: Research Papers Source Type: journals
Satb1 and Satb2 regulate embryonic stem cell differentiation and Nanog expression [Research Papers]Email this article to a colleague.
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Satb1 and the closely related Satb2 proteins regulate gene expression and higher-order chromatin structure of multigene clusters in vivo. In examining the role of Satb proteins in murine embryonic stem (ES) cells, we find that Satb1–/– cells display an impaired differentiation potential and augmented expression of the pluripotency determinants Nanog, Klf4, and Tbx3. Metastable states of self-renewal and differentiation competence have been attributed to heterogeneity of ES cells in the expression of Nanog. Satb1–/– cultures have a higher proportion of Nanoghigh cells, and an increased potential to r...
Source: Genes and Development - November 16, 2009 Category: Genetics & Stem Cells Authors: Savarese, F., Davila, A., Nechanitzky, R., De La Rosa-Velazquez, I., Pereira, C. F., Engelke, R., Takahashi, K., Jenuwein, T., Kohwi-Shigematsu, T., Fisher, A. G., Grosschedl, R. Tags: Research Papers Source Type: journals
Gene loops function to maintain transcriptional memory through interaction with the nuclear pore complex [Research Papers]Email this article to a colleague.
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Inducible genes in yeast retain a "memory" of recent transcriptional activity during periods of short-term repression, allowing them to be reactivated faster when reinduced. This confers a rapid and versatile gene expression response to the environment. We demonstrate that this memory mechanism is associated with gene loop interactions between the promoter and 3' end of the responsive genes HXK1 and GAL1::FMP27. The maintenance of these memory gene loops (MGLs) during intervening periods of transcriptional repression is required for faster RNA polymerase II (Pol II) recruitment to the genes upon reinduction, thereby facili...
Source: Genes and Development - November 16, 2009 Category: Genetics & Stem Cells Authors: Tan-Wong, S. M., Wijayatilake, H. D., Proudfoot, N. J. Tags: Research Papers Source Type: journals
A physiological role for gene loops in yeast [Research Communications]Email this article to a colleague.
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DNA loops that juxtapose the promoter and terminator regions of RNA polymerase II-transcribed genes have been identified in yeast and mammalian cells. Loop formation is transcription-dependent and requires components of the pre-mRNA 3'-end processing machinery. Here we report that looping at the yeast GAL10 gene persists following a cycle of transcriptional activation and repression. Moreover, GAL10 and a GAL1p-SEN1 reporter undergo rapid reactivation kinetics following a cycle of activation and repression—a phenomenon defined as "transcriptional memory"—and this effect correlates with the persistence of loopin...
Source: Genes and Development - November 16, 2009 Category: Genetics & Stem Cells Authors: Laine, J.-P., Singh, B. N., Krishnamurthy, S., Hampsey, M. Tags: Research Communications Source Type: journals
Nonallelic transvection of multiple imprinted loci is organized by the H19 imprinting control region during germline development [Research Communications]Email this article to a colleague.
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Recent observations highlight that the mammalian genome extensively communicates with itself via long-range chromatin interactions. The causal link between such chromatin cross-talk and epigenetic states is, however, poorly understood. We identify here a network of physically juxtaposed regions from the entire genome with the common denominator of being genomically imprinted. Moreover, CTCF-binding sites within the H19 imprinting control region (ICR) not only determine the physical proximity among imprinted domains, but also transvect allele-specific epigenetic states, identified by replication timing patterns, to interact...
Source: Genes and Development - November 16, 2009 Category: Genetics & Stem Cells Authors: Sandhu, K. S., Shi, C., Sjolinder, M., Zhao, Z., Gondor, A., Liu, L., Tiwari, V. K., Guibert, S., Emilsson, L., Imreh, M. P., Ohlsson, R. Tags: Research Communications Source Type: journals
Concomitant suppression of three target genes can explain the impact of a microRNA on metastasis [Research Communications]Email this article to a colleague.
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It remains unclear whether a microRNA (miRNA) affects a given phenotype via concomitant down-regulation of its entire repertoire of targets or instead by suppression of only a modest subset of effectors. We demonstrate that inhibition of breast cancer metastasis by miR-31—a miRNA predicted to modulate >200 mRNAs—can be entirely explained by miR-31's pleiotropic regulation of three targets. Thus, concurrent re-expression of integrin-5, radixin, and RhoA abrogates miR-31-imposed metastasis suppression. These effectors influence distinct steps of the metastatic process. Our findings have implications concerning...
Source: Genes and Development - November 16, 2009 Category: Genetics & Stem Cells Authors: Valastyan, S., Benaich, N., Chang, A., Reinhardt, F., Weinberg, R. A. Tags: Research Communications Source Type: journals
Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been [Reviews]Email this article to a colleague.
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Sterol regulatory element-binding proteins (SREBPs) are a subfamily of basic helix–loop–helix leucine zipper (bHLH-LZ) transcription factors that are conserved from fungi to humans and are defined by two key features: a signature tyrosine residue in the DNA-binding domain, and a membrane-tethering domain that is a target for regulated proteolysis. Recent studies including genome-wide and model organism approaches indicate SREBPs coordinate cellular lipid metabolism with other cellular physiologic processes. These functions are broadly related as cellular adaptation to environmental changes ranging from nutrient...
Source: Genes and Development - November 16, 2009 Category: Genetics & Stem Cells Authors: Osborne, T. F., Espenshade, P. J. Tags: Development, Molecular Physiology and Metabolism Reviews Source Type: journals
Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis [Reviews]Email this article to a colleague.
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The epithelium of the mammary gland exists in a highly dynamic state, undergoing dramatic morphogenetic changes during puberty, pregnancy, lactation, and regression. The recent identification of stem and progenitor populations in mouse and human mammary tissue has provided evidence that the mammary epithelium is organized in a hierarchical manner. Characterization of these normal epithelial subtypes is an important step toward understanding which cells are predisposed to oncogenesis. This review summarizes progress in the field toward defining constituent cells and key molecular regulators of the mammary epithelial hierarc...
Source: Genes and Development - November 16, 2009 Category: Genetics & Stem Cells Authors: Visvader, J. E. Tags: Cancer and Disease Models Reviews Source Type: journals
Enzymatic regulation of pattern: BMP4 binds CUB domains of Tolloids and inhibits proteinase activity [Research Papers]Email this article to a colleague.
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In Xenopus embryos, a dorsal–ventral patterning gradient is generated by diffusing Chordin/bone morphogenetic protein (BMP) complexes cleaved by BMP1/Tolloid metalloproteinases in the ventral side. We developed a new BMP1/Tolloid assay using a fluorogenic Chordin peptide substrate and identified an unexpected negative feedback loop for BMP4, in which BMP4 inhibits Tolloid enzyme activity noncompetitively. BMP4 binds directly to the CUB (Complement 1r/s, Uegf [a sea urchin embryonic protein] and BMP1) domains of BMP1 and Drosophila Tolloid with high affinity. Binding to CUB domains inhibits BMP4 signaling. These findi...
Source: Genes and Development - November 2, 2009 Category: Genetics & Stem Cells Authors: Lee, H. X., Mendes, F. A., Plouhinec, J.-L., De Robertis, E. M. Tags: Research Papers Source Type: journals
Remodeling of the pioneer translation initiation complex involves translation and the karyopherin importin {beta} [Research Papers]Email this article to a colleague.
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Mammalian mRNAs lose and acquire proteins throughout their life span while undergoing processing, transport, translation, and decay. How translation affects messenger RNA (mRNA)–protein interactions is largely unknown. The pioneer round of translation uses newly synthesized mRNA that is bound by cap-binding protein 80 (CBP80)–CBP20 (also known as the cap-binding complex [CBC]) at the cap, poly(A)-binding protein N1 (PABPN1) and PABPC1 at the poly(A) tail, and, provided biogenesis involves pre-mRNA splicing, exon junction complexes (EJCs) at exon–exon junctions. Subsequent rounds of translation engage mRNA...
Source: Genes and Development - November 2, 2009 Category: Genetics & Stem Cells Authors: Sato, H., Maquat, L. E. Tags: Research Papers Source Type: journals
Elucidation of the transcription network governing mammalian sex determination by exploiting strain-specific susceptibility to sex reversal [Research Papers]Email this article to a colleague.
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Despite the identification of some key genes that regulate sex determination, most cases of disorders of sexual development remain unexplained. Evidence suggests that the sexual fate decision in the developing gonad depends on a complex network of interacting factors that converge on a critical threshold. To elucidate the transcriptional network underlying sex determination, we took the first expression quantitative trait loci (eQTL) approach in a developing organ. We identified reproducible differences in the transcriptome of the embryonic day 11.5 (E11.5) XY gonad between C57BL/6J (B6) and 129S1/SvImJ (129S1), indicating...
Source: Genes and Development - November 2, 2009 Category: Genetics & Stem Cells Authors: Munger, S. C., Aylor, D. L., Syed, H. A., Magwene, P. M., Threadgill, D. W., Capel, B. Tags: Research Papers Source Type: journals
Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells [Research Papers]Email this article to a colleague.
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The histone H3 Lys 9 (H3K9) methyltransferase Eset is an epigenetic regulator critical for the development of the inner cell mass (ICM). Although ICM-derived embryonic stem (ES) cells are normally unable to contribute to the trophectoderm (TE) in blastocysts, we find that depletion of Eset by shRNAs leads to differentiation with the formation of trophoblast-like cells and induction of trophoblast-associated gene expression. Using chromatin immmunoprecipitation (ChIP) and sequencing (ChIP-seq) analyses, we identified Eset target genes with Eset-dependent H3K9 trimethylation. We confirmed that genes that are preferentially e...
Source: Genes and Development - November 2, 2009 Category: Genetics & Stem Cells Authors: Yuan, P., Han, J., Guo, G., Orlov, Y. L., Huss, M., Loh, Y.-H., Yaw, L.-P., Robson, P., Lim, B., Ng, H.-H. Tags: Research Papers Source Type: journals
A novel membrane fusion-mediated plant immunity against bacterial pathogens [Research Papers]Email this article to a colleague.
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Plants have developed their own defense strategies because they have no immune cells. A common plant defense strategy involves programmed cell death (PCD) at the infection site, but how the PCD-associated cell-autonomous immunity is executed in plants is not fully understood. Here we provide a novel mechanism underlying cell-autonomous immunity, which involves the fusion of membranes of a large central vacuole with the plasma membrane, resulting in the discharge of vacuolar antibacterial proteins to the outside of the cells, where bacteria proliferate. The extracellular fluid that was discharged from the vacuoles of infect...
Source: Genes and Development - November 2, 2009 Category: Genetics & Stem Cells Authors: Hatsugai, N., Iwasaki, S., Tamura, K., Kondo, M., Fuji, K., Ogasawara, K., Nishimura, M., Hara-Nishimura, I. Tags: Research Papers Source Type: journals
The dosage compensation complex shapes the conformation of the X chromosome in Drosophila [Research Communications]Email this article to a colleague.
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The dosage compensation complex (DCC) in Drosophila globally increases transcription from the X chromosome in males to compensate for its monosomy. We discovered a male-specific conformation of the X chromosome that depends on the associations of high-affinity binding sites (HAS) of the DCC. The core DCC subunits MSL1–MSL2 are responsible for this male-specific organization. Contrary to emerging concepts, we found that neither DCC assembly nor the conformation of the male X chromosome are influenced by nuclear pore components. We propose that nuclear organization of HAS is central to the faithful distribution of the ...
Source: Genes and Development - November 2, 2009 Category: Genetics & Stem Cells Authors: Grimaud, C., Becker, P. B. Tags: Research Communications Source Type: journals
SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state [Research Communications]Email this article to a colleague.
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Transcription factors that play key roles in regulating embryonic stem (ES) cell state have been identified, but the chromatin regulators that help maintain ES cells are less well understood. A high-throughput shRNA screen was used to identify novel chromatin regulators that influence ES cell state. Loss of histone H3 Lys 9 (H3K9) methyltransferases, particularly SetDB1, had the most profound effects on ES cells. Chromatin immunoprecipitation (ChIP) coupled with massively parallel DNA sequencing (ChIP-Seq) and functional analysis revealed that SetDB1 and histone H3K9-methylated nucleosomes occupy and repress genes encoding...
Source: Genes and Development - November 2, 2009 Category: Genetics & Stem Cells Authors: Bilodeau, S., Kagey, M. H., Frampton, G. M., Rahl, P. B., Young, R. A. Tags: Research Communications Source Type: journals
PiggyMac, a domesticated piggyBac transposase involved in programmed genome rearrangements in the ciliate Paramecium tetraurelia [Research Communications]Email this article to a colleague.
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Programmed genome rearrangements drive functional gene assembly in ciliates during the development of the somatic macronucleus. The elimination of germline sequences is directed by noncoding RNAs and is initiated by DNA double-strand breaks, but the enzymes responsible for DNA cleavage have not been identified. We show here that PiggyMac (Pgm), a domesticated piggyBac transposase, is required for these rearrangements in Paramecium tetraurelia. A GFP-Pgm fusion localizes in developing macronuclei, where rearrangements take place, and RNAi-mediated silencing of PGM abolishes DNA cleavage. This is the first in vivo evidence s...
Source: Genes and Development - November 2, 2009 Category: Genetics & Stem Cells Authors: Baudry, C., Malinsky, S., Restituito, M., Kapusta, A., Rosa, S., Meyer, E., Betermier, M. Tags: Research Communications Source Type: journals
Endoreplication: polyploidy with purpose [Reviews]Email this article to a colleague.
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A great many cell types are necessary for the myriad capabilities of complex, multicellular organisms. One interesting aspect of this diversity of cell type is that many cells in diploid organisms are polyploid. This is called endopolyploidy and arises from cell cycles that are often characterized as "variant," but in fact are widespread throughout nature. Endopolyploidy is essential for normal development and physiology in many different organisms. Here we review how both plants and animals use variations of the cell cycle, termed collectively as endoreplication, resulting in polyploid cells that support specific aspects ...
Source: Genes and Development - November 2, 2009 Category: Genetics & Stem Cells Authors: Lee, H. O., Davidson, J. M., Duronio, R. J. Tags: Cell Cycle and DNA Replication Reviews Source Type: journals
Subtraction by addition: domesticated transposases in programmed DNA elimination [Perspectives]Email this article to a colleague.
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The ciliate Paramecium tetraurelia must eliminate ~60,000 short sequences from its genome to generate uninterrupted coding sequences in its somatic macronucleus. In this issue of Genes & Development, Baudry and colleagues (pp. 2478–2483) identify the protein that excises these noncoding sequences: a domesticated piggyBac transposase that has been adapted to remove what are likely the remnants of transposon insertions. This new study reveals how addition of a transposase to small RNA-directed silencing machinery can guide major genome reorganization. (Source: Genes and Development)
Source: Genes and Development - November 2, 2009 Category: Genetics & Stem Cells Authors: Motl, J. A., Chalker, D. L. Tags: DNA Recombination and Repair, Post-transcriptional Control Perspectives Source Type: journals
A kiss of death--proteasome-mediated membrane fusion and programmed cell death in plant defense against bacterial infection [Perspectives]Email this article to a colleague.
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Eukaryotes have evolved various means for controlled and organized cellular destruction, known as programmed cell death (PCD). In plants, PCD is a crucial regulatory mechanism in multiple physiological processes, including terminal differentiation, senescence, and disease resistance. In this issue of Genes & Development, Hatsugai and colleagues (pp. 2496–2506) demonstrate a novel plant defense strategy to trigger bacteria-induced PCD, involving proteasome-dependent tonoplast and plasma membrane fusion followed by discharge of vacuolar antimicrobial and death-inducing contents into the apoplast. (Source: Genes and Development)
Source: Genes and Development - November 2, 2009 Category: Genetics & Stem Cells Authors: Pajerowska-Mukhtar, K., Dong, X. Tags: Plant Biology, Bacteria and Viruses Perspectives Source Type: journals
Allelic inactivation of rDNA loci [Research Papers]Email this article to a colleague.
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Human cells contain several hundred ribosomal genes (rDNA) that are clustered into nucleolar organizer regions (NORs) on the short arms of five different acrocentric chromosomes. Only ~50% of the gene copies are actually expressed in somatic cells. Here, we used a new cytological technique to demonstrate that rDNA is regulated allelically in a regional manner, with one parental copy of each NOR being repressed in any individual cell. This process is similar to that of X-chromosome inactivation in females. Early in development, one copy of each NOR becomes late-replicating, thus probably marking it for inactivation and subs...
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Schlesinger, S., Selig, S., Bergman, Y., Cedar, H. Tags: Research Papers Source Type: journals
Reduced capacity of alternative {sigma}s to melt promoters ensures stringent promoter recognition [Research Papers]Email this article to a colleague.
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In bacteria, multiple s direct RNA polymerase to distinct sets of promoters. Housekeeping s direct transcription from thousands of promoters, whereas most alternative s are more selective, recognizing more highly conserved promoter motifs. For 32 and 28, two Escherichia coli Group 3 s, altering a few residues in Region 2.3, the portion of implicated in promoter melting, to those universally conserved in housekeeping s relaxed their stringent promoter requirements and significantly enhanced melting of suboptimal promoters. All Group 3 s and the more divergent Group 4 s have nonconserved amino acids at these positions and ra...
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Koo, B.-M., Rhodius, V. A., Nonaka, G., deHaseth, P. L., Gross, C. A. Tags: Research Papers Source Type: journals
The SIOD disorder protein SMARCAL1 is an RPA-interacting protein involved in replication fork restart [Research Papers]Email this article to a colleague.
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The integrity of genomic DNA is continuously challenged by the presence of DNA base lesions or DNA strand breaks. Here we report the identification of a new DNA damage response protein, SMARCAL1 (SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin, subfamily a-like 1), which is a member of the SNF2 family and is mutated in Schimke immunoosseous dysplasia (SIOD). We demonstrate that SMARCAL1 directly interacts with Replication protein A (RPA) and is recruited to sites of DNA damage in an RPA-dependent manner. SMARCAL1-depleted cells display sensitivity to DNA-damaging agents that induce replication fo...
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Ciccia, A., Bredemeyer, A. L., Sowa, M. E., Terret, M.-E., Jallepalli, P. V., Harper, J. W., Elledge, S. J. Tags: Research Papers Source Type: journals
The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks [Research Papers]Email this article to a colleague.
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Mutations in SMARCAL1 (HARP) cause Schimke immunoosseous dysplasia (SIOD). The mechanistic basis for this disease is unknown. Using functional genomic screens, we identified SMARCAL1 as a genome maintenance protein. Silencing and overexpression of SMARCAL1 leads to activation of the DNA damage response during S phase in the absence of any genotoxic agent. SMARCAL1 contains a Replication protein A (RPA)-binding motif similar to that found in the replication stress response protein TIPIN (Timeless-Interacting Protein), which is both necessary and sufficient to target SMARCAL1 to stalled replication forks. RPA binding is crit...
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Bansbach, C. E., Betous, R., Lovejoy, C. A., Glick, G. G., Cortez, D. Tags: Research Papers Source Type: journals
The annealing helicase HARP is recruited to DNA repair sites via an interaction with RPA [Research Communications]Email this article to a colleague.
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HepA-related protein (HARP) (also known as SMARCAL1) is an ATP-driven annealing helicase that catalyzes the formation of dsDNA from complementary Replication protein A (RPA)-bound ssDNA. Here we find that HARP contains a conserved N-terminal motif that is necessary and sufficient for binding to RPA. This RPA-binding motif is not required for annealing helicase activity, but is essential for the recruitment of HARP to sites of laser-induced DNA damage. These findings suggest that the interaction of HARP with RPA increases the concentration of annealing helicase activity in the vicinity of ssDNA regions to facilitate process...
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Yusufzai, T., Kong, X., Yokomori, K., Kadonaga, J. T. Tags: Research Communications Source Type: journals
The annealing helicase HARP protects stalled replication forks [Research Communications]Email this article to a colleague.
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Mutations in HepA-related protein (HARP) are the only identified causes of Schimke immunoosseous dysplasia (SIOD). HARP has a unique annealing helicase activity in vitro, but the in vivo functional significance remains unknown. Here, we demonstrated that HARP is recruited to stalled replication forks via its direct interaction with Replication protein A (RPA). Cells with HARP depletion displayed increased spontaneous DNA damage and G2/M arrest, suggesting that HARP normally acts to stabilize stalled replication forks. Our data place the annealing helicase activity of HARP at replication forks and propose that SIOD syndrome...
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Yuan, J., Ghosal, G., Chen, J. Tags: Research Communications Source Type: journals
miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A [Research Communications]Email this article to a colleague.
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The Rb–E2F pathway drives cell cycle progression and cell proliferation, and the molecular strategies safeguarding its activity are not fully understood. Here we report that E2F1 directly transactivates miR-449a/b. miR-449a/b targets and inhibits oncogenic CDK6 and CDC25A, resulting in pRb dephosphorylation and cell cycle arrest at G1 phase, revealing a negative feedback regulation of the pRb–E2F1 pathway. Moreover, miR-449a/b expression in cancer cells is epigenetically repressed through histone H3 Lys27 trimethylation, and epigenetic drug treatment targeting histone methylation results in strong induction of ...
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Yang, X., Feng, M., Jiang, X., Wu, Z., Li, Z., Aau, M., Yu, Q. Tags: Research Communications Source Type: journals
Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A [Research Communications]Email this article to a colleague.
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Mammary alveologenesis is abrogated in the absence of the transcription factors STAT5A/5B, which mediate cytokine signaling. To reveal the underlying causes for this developmental block, we studied mammary stem and progenitor cells. While loss of STAT5A/5B did not affect the stem cell population and its ability to form mammary ducts, luminal progenitors were greatly reduced and unable to form alveoli during pregnancy. Temporally controlled expression of transgenic STAT5A in mammary epithelium lacking STAT5A/5B restored the luminal progenitor population and rescued alveologenesis in a reversible fashion in vivo. Thus, STAT5...
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Yamaji, D., Na, R., Feuermann, Y., Pechhold, S., Chen, W., Robinson, G. W., Hennighausen, L. Tags: Research Communications Source Type: journals
Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development [Research Communications]Email this article to a colleague.
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Common lymphoid progenitors (CLPs) clonally produce both B- and T-cell lineages, but have little myeloid potential in vivo. However, some studies claim that the upstream lymphoid-primed multipotent progenitor (LMPP) is the thymic seeding population, and suggest that CLPs are primarily B-cell-restricted. To identify surface proteins that distinguish functional CLPs from B-cell progenitors, we used a new computational method of Mining Developmentally Regulated Genes (MiDReG). We identified Ly6d, which divides CLPs into two distinct populations: one that retains full in vivo lymphoid potential and produces more thymocytes at ...
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Inlay, M. A., Bhattacharya, D., Sahoo, D., Serwold, T., Seita, J., Karsunky, H., Plevritis, S. K., Dill, D. L., Weissman, I. L. Tags: Research Communications Source Type: journals
Promoter recognition by bacterial alternative {sigma} factors: the price of high selectivity? [Perspectives]Email this article to a colleague.
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A key step in bacterial transcription initiation is melting of the double-stranded promoter DNA by the RNA polymerase holoenzyme. Primary factors mediate the melting of thousands of promoters through a conserved set of aromatic amino acids. Alternative s, which direct transcription of restricted regulons, lack the full set of melting residues. In this issue of Genes & Development, Koo and colleagues (pp. 2426–2436) show that introducing the primary melting residues into alternative s relaxes their promoter specificity, pointing to a trade-off of reduced promoter melting capacity for increased promoter stringency....
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Feklistov, A., Darst, S. A. Tags: Chromatin and Gene Expression, Bacteria and Viruses Perspectives Source Type: journals
Developmental trajectories in early hematopoiesis [Perspectives]Email this article to a colleague.
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The paths that hematopoietic stem cells take to develop from multipotent, self-renewing cells into committed lymphocytes has been a topic of debate for some time. During early hematopoiesis, multiple branchpoints have been described in which progeny cells segregate into cell lineages with distinct developmental potentials. In this issue of Genes & Development, Inlay and colleagues (pp. 2376–2381) identify novel intermediate stages through which hematopoietic progenitor cells travel. (Source: Genes and Development)
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Murre, C. Tags: Immunology, Development Perspectives Source Type: journals
HARPing on about the DNA damage response during replication [Perspectives]Email this article to a colleague.
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In this issue of Genes & Development, four papers report that the annealing helicase HepA-related protein (HARP, also known as SMARCAL1 [SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1]) binds directly to the ssDNA-binding protein Replication protein A (RPA) and is recruited to sites of replicative stress. Knockdown of HARP results in hypersensitivity to multiple DNA-damaging agents and defects in fork stability or restart. These exciting insights reveal a key new player in the S-phase DNA damage response. (Source: Genes and Development)
Source: Genes and Development - October 15, 2009 Category: Genetics & Stem Cells Authors: Driscoll, R., Cimprich, K. A. Tags: DNA Recombination and Repair, Cell Cycle and DNA Replication Perspectives Source Type: journals
Erratum: Transcription is required for establishment of germline methylation marks at imprinted genes [Errata]Email this article to a colleague.
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(Source: Genes and Development)
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Chotalia, M., Smallwood, S. A., Ruf, N., Dawson, C., Lucifero, D., Frontera, M., James, K., Dean, W., Kelsey, G. Tags: Errata Source Type: journals
The Scc2/Scc4 cohesin loader determines the distribution of cohesin on budding yeast chromosomes [Research Papers]Email this article to a colleague.
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Cohesins mediate sister chromatid cohesion and DNA repair and also function in gene regulation. Chromosomal cohesins are distributed nonrandomly, and their deposition requires the heterodimeric Scc2/Scc4 loader. Whether Scc2/Scc4 establishes nonrandom cohesin distributions on chromosomes is poorly characterized, however. To better understand the spatial regulation of cohesin association, we mapped budding yeast Scc2 and Scc4 chromosomal distributions. We find that Scc2/Scc4 resides at previously mapped cohesin-associated regions (CARs) in pericentromeric and arm regions, and that Scc2/Scc4–cohesin colocalization pers...
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Kogut, I., Wang, J., Guacci, V., Mistry, R. K., Megee, P. C. Tags: Research Papers Source Type: journals
Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila [Research Papers]Email this article to a colleague.
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Gut homeostasis is controlled by both immune and developmental mechanisms, and its disruption can lead to inflammatory disorders or cancerous lesions of the intestine. While the impact of bacteria on the mucosal immune system is beginning to be precisely understood, little is known about the effects of bacteria on gut epithelium renewal. Here, we addressed how both infectious and indigenous bacteria modulate stem cell activity in Drosophila. We show that the increased epithelium renewal observed upon some bacterial infections is a consequence of the oxidative burst, a major defense of the Drosophila gut. Additionally, we p...
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Buchon, N., Broderick, N. A., Chakrabarti, S., Lemaitre, B. Tags: Research Papers Source Type: journals
A heritable switch in carbon source utilization driven by an unusual yeast prion [Research Papers]Email this article to a colleague.
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We report a prion that makes cells resistant to the glucose-associated repression of alternative carbon sources, [GAR+] (for "resistant to glucose-associated repression," with capital letters indicating dominance and brackets indicating its non-Mendelian character). [GAR+] appears spontaneously at a high rate and is transmissible by non-Mendelian, cytoplasmic inheritance. Several lines of evidence suggest that the prion state involves a complex between a small fraction of the cellular complement of Pma1, the major plasma membrane proton pump, and Std1, a much lower-abundance protein that participates in glucose signaling. ...
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Brown, J. C.S., Lindquist, S. Tags: Research Papers Source Type: journals
Transcription factor choice in the Hippo signaling pathway: homothorax and yorkie regulation of the microRNA bantam in the progenitor domain of the Drosophila eye imaginal disc [Research Papers]Email this article to a colleague.
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The accurate control of cell proliferation and survival is critical for animal development. The Hippo tumor suppressor pathway regulates both of these parameters by controlling the nuclear availability of the transcriptional coactivator Yorkie (Yki), which regulates downstream target genes together with Scalloped (Sd), a DNA-binding protein. Here we provide evidence that Yki can also regulate target genes in conjunction with Homothorax (Hth) and Teashirt (Tsh), two DNA-binding transcription factors expressed in the uncommitted progenitor cells of the Drosophila eye imaginal disc. Clonal analyses demonstrate that Hth and Ts...
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Peng, H. W., Slattery, M., Mann, R. S. Tags: Research Papers Source Type: journals
XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy [Research Papers]Email this article to a colleague.
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Mutations in superoxide dismutase-1 (SOD1) cause familial amyotrophic lateral sclerosis (fALS). Recent evidence implicates adaptive responses to endoplasmic reticulum (ER) stress in the disease process via a pathway known as the unfolded protein response (UPR). Here, we investigated the contribution to fALS of X-box-binding protein-1 (XBP-1), a key UPR transcription factor that regulates genes involved in protein folding and quality control. Despite expectations that XBP-1 deficiency would enhance the pathogenesis of mutant SOD1, we observed a dramatic decrease in its toxicity due to an enhanced clearance of mutant SOD1 ag...
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Hetz, C., Thielen, P., Matus, S., Nassif, M., Court, F., Kiffin, R., Martinez, G., Cuervo, A. M., Brown, R. H., Glimcher, L. H. Tags: Research Papers Source Type: journals
An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons [Research Papers]Email this article to a colleague.
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Neuronal depolarization and CaM kinase IV signaling alter the splicing of multiple exons in transcripts for ion channels, neurotransmitter receptors, and other synaptic proteins. These splicing changes are mediated in part by special CaM kinase-responsive RNA elements, within or adjacent to exons that are repressed in the initial phase of chronic depolarization. The splicing of many neuronal transcripts is also regulated by members of the Fox (Feminizing gene on X) protein family, and these Fox targets are also often proteins affecting synaptic activity. We show that Fox-1/Ataxin 2-Binding Protein 1 (A2BP1), a protein impl...
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Lee, J.-A., Tang, Z.-Z., Black, D. L. Tags: Research Papers Source Type: journals
Integrin-linked kinase controls vascular wall formation by negatively regulating Rho/ROCK-mediated vascular smooth muscle cell contraction [Research Communications]Email this article to a colleague.
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Vascular smooth muscle cells (VSMCs) form contractile layers around larger blood vessels in a process that is essential for the formation of a fully functional vasculature. Here, we show that integrin-linked kinase (ILK) is required for the formation of a unitary layer of aligned VSMCs around arterioles and the regulation of blood vessel constriction in mice. In the absence of ILK, activated Rho/ROCK signaling induces the elevated phosphorylation of myosin light chain leading to abnormally enhanced VSMC contraction in vitro and in vivo. Our findings identify ILK as a key component regulating vascular wall formation by nega...
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Kogata, N., Tribe, R. M., Fassler, R., Way, M., Adams, R. H. Tags: Research Communications Source Type: journals
Chemokine signaling guides regional patterning of the first embryonic artery [Research Communications]Email this article to a colleague.
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The aorta traverses the body, yet little is known about how it is patterned in different anatomical locations. Here, we show that the aorta develops from genetically distinct endothelial cells originating from diverse locations within the embryo. Furthermore, chemokine (C-X-C motif) receptor 4a (cxcr4a) is restricted to endothelial cells derived from anterior mesoderm, and is required specifically for formation of the lateral aortae. Cxcl12b, a cxcr4a ligand, is expressed in endoderm underlying the lateral aortae, and loss of cxcl12b phenocopies cxcr4a deficiency. These studies reveal unexpected endothelial diversity withi...
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Siekmann, A. F., Standley, C., Fogarty, K. E., Wolfe, S. A., Lawson, N. D. Tags: Research Communications Source Type: journals
Long-range spreading of dosage compensation in Drosophila captures transcribed autosomal genes inserted on X [Research Communications]Email this article to a colleague.
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Dosage compensation in Drosophila melanogaster males is achieved via targeting of male-specific lethal (MSL) complex to X-linked genes. This is proposed to involve sequence-specific recognition of the X at ~150–300 chromatin entry sites, and subsequent spreading to active genes. Here we ask whether the spreading step requires transcription and is sequence-independent. We find that MSL complex binds, acetylates, and up-regulates autosomal genes inserted on X, but only if transcriptionally active. We conclude that a long-sought specific DNA sequence within X-linked genes is not obligatory for MSL binding. Instead, link...
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Gorchakov, A. A., Alekseyenko, A. A., Kharchenko, P., Park, P. J., Kuroda, M. I. Tags: Research Communications Source Type: journals
Bacterial-modulated host immunity and stem cell activation for gut homeostasis [Perspectives]Email this article to a colleague.
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Although it is widely accepted that dynamic cross-talk between gut epithelia and microorganisms must occur to achieve gut homeostasis, the critical mechanisms by which gut–microbe interactions are regulated remain uncertain. In this issue of Genes & Development, Buchon and colleagues (pp. 2333–2344) revealed that the reaction of the gut to microorganisms is not restricted to activating immune systems, but extends to integrated responses essential for gut tissue homeostasis, including self-renewal and the differentiation of stem cells. Further investigation of the connection between immune response and stem ...
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Lee, W.-J. Tags: Immunology, Development, Bacteria and Viruses Perspectives Source Type: journals
Autophagy for the avoidance of neurodegeneration [Perspectives]Email this article to a colleague.
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Cellular defense mechanisms, including the unfolded protein response (UPR) and autophagy, attempt to resolve toxic protein aggregates, which are common denominators of neurodegenerative diseases. In this issue of Genes & Development, Hetz and colleagues (pp. 2294–2306) surprisingly show that inhibition of the UPR by knockout of XBP-1 causes a massive increase in autophagy, enhances clearance of superoxide dismutase 1 (SOD1) aggregates, and delays the development of amyotrophic lateral sclerosis. These findings suggest the existence of a homeostatic—if not hormetic—balance between distinct cellular def...
Source: Genes and Development - October 1, 2009 Category: Genetics & Stem Cells Authors: Madeo, F., Eisenberg, T., Kroemer, G. Tags: Cell Death, Neurobiology Perspectives Source Type: journals
Ipl1/Aurora B kinase coordinates synaptonemal complex disassembly with cell cycle progression and crossover formation in budding yeast meiosis [Research Papers]Email this article to a colleague.
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Several protein kinases collaborate to orchestrate and integrate cellular and chromosomal events at the G2/M transition in both mitotic and meiotic cells. During the G2/M transition in meiosis, this includes the completion of crossover recombination, spindle formation, and synaptonemal complex (SC) breakdown. We identified Ipl1/Aurora B kinase as the main regulator of SC disassembly. Mutants lacking Ipl1 or its kinase activity assemble SCs with normal timing, but fail to dissociate the central element component Zip1, as well as its binding partner, Smt3/SUMO, from chromosomes in a timely fashion. Moreover, lack of Ipl1 act...
Source: Genes and Development - September 15, 2009 Category: Genetics & Stem Cells Authors: Jordan, P., Copsey, A., Newnham, L., Kolar, E., Lichten, M., Hoffmann, E. Tags: Research Papers Source Type: journals
Releasing cohesin from chromosome arms in early mitosis: opposing actions of Wapl-Pds5 and Sgo1 [Research Papers]Email this article to a colleague.
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The cohesin complex establishes sister chromatid cohesion during S phase. In metazoan cells, most if not all cohesin dissociates from chromatin during mitotic prophase, leading to the formation of metaphase chromosomes with two cytologically discernible chromatids. This process, known as sister chromatid resolution, is believed to be a prerequisite for synchronous separation of sister chromatids in subsequent anaphase. To dissect this process at a mechanistic level, we set up an in vitro system. Sister chromatid resolution is severely impaired upon depletion of Wapl from Xenopus egg extracts. Exogenously added human Wapl c...
Source: Genes and Development - September 15, 2009 Category: Genetics & Stem Cells Authors: Shintomi, K., Hirano, T. Tags: Research Papers Source Type: journals
TBP2 is essential for germ cell development by regulating transcription and chromatin condensation in the oocyte [Research Papers]Email this article to a colleague.
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Development of the germline requires consecutive differentiation events. Regulation of these has been associated with germ cell-specific and pluripotency-associated transcription factors, but the role of general transcription factors (GTFs) remains elusive. TATA-binding protein (TBP) is a GTF involved in transcription by all RNA polymerases. During ovarian folliculogenesis in mice the vertebrate-specific member of the TBP family, TBP2/TRF3, is expressed exclusively in oocytes. To determine TBP2 function in vivo, we generated TBP2-deficient mice. We found that Tbp2–/– mice are viable with no apparent phenotype. ...
Source: Genes and Development - September 15, 2009 Category: Genetics & Stem Cells Authors: Gazdag, E., Santenard, A., Ziegler-Birling, C., Altobelli, G., Poch, O., Tora, L., Torres-Padilla, M.-E. Tags: Research Papers Source Type: journals
Negative feedback maintenance of heme homeostasis by its receptor, Rev-erb{alpha} [Research Papers]Email this article to a colleague.
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Intracellular heme levels must be tightly regulated to maintain proper mitochondrial respiration while minimizing toxicity, but the homeostatic mechanisms are not well understood. Here we report a novel negative feedback mechanism whereby the nuclear heme receptor Rev-erb tightly controls the level of its own ligand. Heme binding to Rev-erb recruits the NCoR/histone deacetylase 3 (HDAC3) corepressor complex to repress the transcription of the coactivator PGC-1, a potent inducer of heme synthesis. Depletion of Rev-erb derepresses PGC-1, resulting in increased heme levels. Conversely, increased Rev-erb reduces intracellular ...
Source: Genes and Development - September 15, 2009 Category: Genetics & Stem Cells Authors: Wu, N., Yin, L., Hanniman, E. A., Joshi, S., Lazar, M. A. Tags: Research Papers Source Type: journals
Phosphorylation modulates rapid nucleocytoplasmic shuttling and cytoplasmic accumulation of Neurospora clock protein FRQ on a circadian time scale [Research Papers]Email this article to a colleague.
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We present a mathematical model that describes the cytoplasmic accumulation of wild-type and mutant FRQ on a circadian time scale on the basis of frequency-modulated rapid nucleocytoplasmic shuttling cycles. (Source: Genes and Development)
Source: Genes and Development - September 15, 2009 Category: Genetics & Stem Cells Authors: Diernfellner, A. C.R., Querfurth, C., Salazar, C., Hofer, T., Brunner, M. Tags: Research Papers Source Type: journals
