Publications from researchers at the Buck Institute for Research on Aging http://www.buckinstitute.org/lunyakLab © 2011 Buck Institute, All Rights Reserved SUMMARY: While some histone modification ChIPseq signals show abrupt peaks across narrow and specific genomic locations, others have diffuse distributions along chromosomes, and their large contiguous enrichment landscapes are better modeled as broad peaks. Here we present BroadPeak, an algorithm for the identification of such broad peaks from diffuse ChIPseq datasets. We show that BroadPeak is a linear time algorithm that requires only two parameters, and we validate its performance on real and simulated histone modification ChIPseq datasets. BroadPeak calls peaks that are highly coincident with both the underlying ChIPseq tag count distributions and relevant biological features, such as the gene bodies of actively transcribed genes, and it shows superior overall recall and precision of known broad peaks from simulated datasets. AVAILABILITY: The source code and documentations are available at http://jordan.biology.gatech.edu/page/software/broadpeak/ CONTACT: king.jordanbiology.gatech.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. http://www.ncbi.nlm.nih.gov/pubmed/23300134 Mon, 31 Dec 2012 00:00:00 -0800 Cellular senescence is associated with global chromatin changes, altered gene expression, and activation of chronic DNA damage signaling. These events ultimately lead to morphological and physiological transformations in primary cells. In this study, we show that chronic DNA damage signals caused by genotoxic stress impact the expression of histones H2A family members and lead to their depletion in the nuclei of senescent human fibroblasts. Our data reinforce the hypothesis that progressive chromatin destabilization may lead to the loss of epigenetic information and impaired cellular function associated with chronic DNA damage upon drugevoked senescence. We propose that changes in the histone biosynthesis and chromatin assembly may directly contribute to cellular aging. In addition, we also outline the method that allows for quantitative and unbiased measurement of these changes. http://www.ncbi.nlm.nih.gov/pubmed/23235539 Sat, 31 Dec 2011 00:00:00 -0800 We report on the development of an unsupervised algorithm for the genomewide discovery and analysis of chromatin signatures. Our Chromatinprofile Alignment followed by Treeclustering algorithm (ChAT) employs dynamic programming of combinatorial histone modification profiles to identify locally similar chromatin subregions and provides complementary utility with respect to existing methods. We applied ChAT to genomic maps of 39 histone modifications in human CD4() T cells to identify both known and novel chromatin signatures. ChAT was able to detect chromatin signatures previously associated with transcription start sites and enhancers as well as novel signatures associated with a variety of regulatory elements. Promoterassociated signatures discovered with ChAT indicate that complex chromatin signatures, made up of numerous colocated histone modifications, facilitate celltype specific gene expression. The discovery of novel L1 retrotransposonassociated bivalent chromatin signatures suggests that these elements influence the monoallelic expression of human genes by shaping the chromatin environment of imprinted genomic regions. Analysis of long geneassociated chromatin signatures point to a role for the H4K20me1 and H3K79me3 histone modifications in transcriptional pause release. The novel chromatin signatures and functional associations uncovered by ChAT underscore the ability of the algorithm to yield novel insight on chromatinbased regulatory mechanisms. http://www.ncbi.nlm.nih.gov/pubmed/22989711 Sat, 31 Dec 2011 00:00:00 -0800 Emerging evidence is shedding light on a large and complex network of epigenetic modifications at play in human stem cells. This "epigenetic landscape" governs the finetuning and precision of gene expression programs that define the molecular basis of stem cell pluripotency, differentiation and reprogramming. This review will focus on recent progress in our understanding of the processes that govern this landscape in stem cells, such as histone modification, DNA methylation, alterations of chromatin structure due to chromatin remodeling and noncoding RNA activity. Further investigation into stem cell epigenetics promises to provide novel advances in the diagnosis and treatment of a wide array of human diseases. http://www.ncbi.nlm.nih.gov/pubmed/22805743 Sat, 31 Dec 2011 00:00:00 -0800 It is currently thought that small RNA (sRNA) based repression mechanisms are primarily employed to mitigate the mutagenic threat posed by the activity of transposable elements (TEs). This can be achieved by the sRNA guided processing of TE transcripts via Dicerdependent (e.g., siRNA) or Dicerindependent (e.g., piRNA) mechanisms. For example, potentially active human L1 elements are silenced by mRNA cleavage induced by element encoded siRNAs, leading to a negative correlation between element mRNA and siRNA levels. On the other hand, there is emerging evidence that TE derived sRNAs can also be used to regulate the host genome. Here, we evaluated these two hypotheses for human TEs by comparing the levels of TE derived mRNA and TE sRNA across six tissues. The genome defense hypothesis predicts a negative correlation between TE mRNA and TE sRNA levels, whereas the genome regulatory hypothesis predicts a positive correlation. On average, TE mRNA and TE sRNA levels are positively correlated across human tissues. These correlations are higher than seen for human genes or for randomly permuted control data sets. Overall, Alu subfamilies show the highest positive correlations of element mRNA and sRNA levels across tissues, although a few of the youngest, and potentially most active, Alu subfamilies do show negative correlations. Thus, Alu derived sRNAs may be related to both genome regulation and genome defense. These results are inconsistent with a simple model whereby TE derived sRNAs reduce levels of standing TE mRNA via transcript cleavage, and suggest that human cells efficiently process TE transcripts into sRNA based on the available message levels. This may point to a widespread role for processed TE transcripts in genome regulation or to alternative roles of TEtosRNA processing including the mitigation of TE transcript cytotoxicity. http://www.ncbi.nlm.nih.gov/pubmed/22754749 Sat, 31 Dec 2011 00:00:00 -0800 Recent analyses suggest that transposable elementderived transcripts are processed to yield a variety of small RNA species that play critical functional roles in gene regulation and chromatin organization as well as genome stability and maintenance. Here we report a mass spectrometry analysis of an RNAaffinity complex isolation using a piRNA homologous sequence derived from Alu retrotransposal RNA. Our data point to potential roles for piALU RNAs in DNA repair, cell cycle and chromatin regulations. http://www.ncbi.nlm.nih.gov/pubmed/22754750 Sat, 31 Dec 2011 00:00:00 -0800 DNA methylation of promoter sequences is a repressive epigenetic mark that downregulates gene expression. However, DNA methylation is more prevalent within genebodies than seen for promoters, and genebody methylation has been observed to be positively correlated with gene expression levels. This paradox remains unexplained, and accordingly the role of DNA methylation in genebodies is poorly understood. We addressed the presence and role of human genebody DNA methylation using a metaanalysis of human genomewide methylation, expression and chromatin data sets. Methylation is associated with transcribed regions as genic sequences have higher levels of methylation than intergenic or promoter sequences. We also find that the relationship between genebody DNA methylation and expression levels is nonmonotonic and bellshaped. Midlevel expressed genes have the highest levels of genebody methylation, whereas the most lowly and highly expressed sets of genes both have low levels of methylation. While genebody methylation can be seen to efficiently repress the initiation of intragenic transcription, the vast majority of methylated sites within genes are not associated with intragenic promoters. In fact, highly expressed genes initiate the most intragenic transcription inconsistent with the previously held notion that genebody methylation serves to repress spurious intragenic transcription to allow for efficient transcriptional elongation. These observations lead us to propose a model to explain the presence of human genebody methylation. This model holds that the repression of intragenic transcription by genebody methylation is largely epiphenomenal, and suggests that genebody methylation levels are predominantly shaped via the accessibility of the DNA to methylating enzyme complexes. http://www.ncbi.nlm.nih.gov/pubmed/22577155 Sat, 31 Dec 2011 00:00:00 -0800 Defining the molecular events that precipitate multisystem decline is an important component of aging research. In this issue, Jin etal. (2011) show that increased expression of the histone demethylase, utx1, causes genomewide decreases in histone H3K27 trimethylation, which includes the insulin/IGF1 signaling (IIS) pathway that promotes aging. http://www.ncbi.nlm.nih.gov/pubmed/21803283 Fri, 31 Dec 2010 00:00:00 -0800 Cellular aging is linked to deficiencies in efficient repair of DNA double strand breaks and authentic genome maintenance at the chromatin level. Aging poses a significant threat to adult stem cell function by triggering persistent DNA damage and ultimately cellular senescence. Senescence is often considered to be irreversible process. Moreover, critical genomic regions engaged in the persistent DNA damage accumulation are unknown. Here we report that 65 of naturally occurring repairable DNA damage in selfrenewing adult stem cells occurs in transposable elements. Upregulation of Alu retrotransposon transcription upon exvivo aging causes nuclear cytotoxicity associated with formation of persistent DNA damage foci and loss of efficient DNA repair in pericentric chromatin. This appears due to a failure of recruitment of condensin I and cohesin complexes. Our results demonstrate that cytotoxicity of induced Alu repeats is functionally relevant for the human adult stem cell aging. Stable suppression of Alu transcription can reverse the senescent phenotype, reinstating the cells' selfrenewing properties and increasing their plasticity by altering socalled "master" pluripotency regulators. http://www.ncbi.nlm.nih.gov/pubmed/21862875 Fri, 31 Dec 2010 00:00:00 -0800 A typical eukaryotic genome harbors a rich variety of repetitive elements. The most abundant are retrotransposons, mobile retroelements that utilize reverse transcriptase and an RNA intermediate to relocate to a new location within the cellular genomes. A vast majority of the repetitive mammalian genome content has originated from the retrotransposition of SINE (100300 bp short interspersed nuclear elements that are derived from the structural 7SL RNA or tRNA), LINE (7kb long interspersed nuclear element), and LTR (23 kb long terminal repeats) transposable element superfamilies. Broadly labeled as "evolutionary junkyard" or "fossils", this enigmatic "dark matter" of the genome possesses many yet to be discovered properties. http://www.ncbi.nlm.nih.gov/pubmed/21916613 Fri, 31 Dec 2010 00:00:00 -0800 Boundary elements partition eukaryotic chromatin into active and repressive domains, and can also block regulatory interactions between domains. Boundary elements act via diverse mechanisms making accurate featurebased computational predictions difficult. Therefore, we developed an unbiased algorithm that predicts the locations of human boundary elements based on the genomic distributions of chromatin and transcriptional states, as opposed to any intrinsic characteristics that they may possess. Application of our algorithm to ChIPseq data for histone modifications and RNA Pol IIbinding data in human CD4() T cells resulted in the prediction of 2542 putative chromatin boundary elements genome wide. Predicted boundary elements display two distinct features: first, positionspecific open chromatin and histone acetylation that is coincident with the recruitment of sequencespecific DNAbinding factors such as CTCF, EVI1 and YYI, and second, a directional and gradual increase in histone lysine methylation across predicted boundaries coincident with a gain of expression of noncoding RNAs, including examples of boundaries encoded by tRNA and other noncoding RNA genes. Accordingly, a number of the predicted human boundaries may function via the synergistic action of sequencespecific recruitment of transcription factors leading to noncoding RNA transcriptional interference and the blocking of facultative heterochromatin propagation by transcriptionassociated chromatin remodeling complexes. http://www.ncbi.nlm.nih.gov/pubmed/21930510 Fri, 31 Dec 2010 00:00:00 -0800 Adult stem cells have taken center stage in current research related to regenerative medicine and pharmacogenomic studies seeking new therapeutic interventions. As we learn more about these cells, it is becoming apparent that the next big leap in our understanding of adult stem cell biology and adult stem cell aging will depend on the integration of approaches from various disciplines. Major advances and technological breakthroughs at the crossroad of fields such as biomaterials, genomics, epigenomics, and proteomics will enable the design of better tools to model human diseases, and warrant safe usage of adult stem cells in the clinic. http://www.ncbi.nlm.nih.gov/pubmed/22157189 Fri, 31 Dec 2010 00:00:00 -0800 MOTIVATION: Chromatin immunoprecipitation followed by highthroughput sequencing (ChIPseq) is widely used in biological research. ChIPseq experiments yield many ambiguous tags that can be mapped with equal probability to multiple genomic sites. Such ambiguous tags are typically eliminated from consideration resulting in a potential loss of important biological information. RESULTS: We have developed a Gibbs sampling based algorithm for the genomic mapping of ambiguous sequence tags. Our algorithm relies on the local genomic tag context to guide the mapping of ambiguous tags. The Gibbs sampling procedure we use simultaneously maps ambiguous tags and updates the probabilities used to infer correct tag map positions. We show that our algorithm is able to correctly map more ambiguous tags than existing mapping methods. Our approach is also able to uncover mapped genomic sites from highly repetitive sequences that can not be detected based on unique tags alone, including transposable elements, segmental duplications and pericentromeric regions. This mapping approach should prove to be useful for increasing biological knowledge on the too often neglected repetitive genomic regions. AVAILABILITY: http://esbg.gatech.edu/jordan/software/map CONTACT: king.jordanbiology.gatech.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. http://www.ncbi.nlm.nih.gov/pubmed/20871106 Tue, 31 Aug 2010 00:00:00 -0700 Stem cellbased regenerative medicine holds great promise for repair of diseased tissue. Modern directions in the field of epigenetic research aimed to decipher the epigenetic signals that give stem cells their unique ability to selfrenew and differentiate into different cell types. However, this research is only the tip of the iceberg when it comes to writing an 'epigenetic instruction manual' for the ramification of molecular details of cell commitment and differentiation. In this review, we discuss the impact of the epigenetic research on our understanding of stem cell biology. http://www.ncbi.nlm.nih.gov/pubmed/18632693 Mon, 30 Jun 2008 00:00:00 -0700 One way to modulate transcription is by partitioning the chromatin fiber within the nucleus into the active or inactive domains through the establishment of higherorder chromatin structure. Such subdivision of chromatin implies the existence of insulators and boundaries that delimit differentially regulated chromosomal loci. Recently published data on transcriptional interference from the repeated component of the genome fits the classic definition of insulator/boundary activity. This review discusses the phenomena of transcriptional interference and raises the question about functionality of genomic "junk" along with the need to stimulate a dialogue on how we would define the insulators and boundaries in the light of contemporary data. Rule 19 (a) (Boundaries)"Before the toss, the umpires shall agree the boundary of the field of play with both captains. The boundary shall, if possible, be marked along its whole length" Rules of Cricket. http://www.ncbi.nlm.nih.gov/pubmed/18524562 Sat, 31 May 2008 00:00:00 -0700 Vascular endothelial growth factor D has recently been linked to the control of lymphangiogenesis and lymphatic metastasis. The molecular determinants regulating vegfD gene transcription, however, have not yet been identified. After isolation of 2 kb of 5'flanking DNA of the human vegfD gene, we identified a novel, atypical direct repeat (DR) element consisting of a consensus halfsite (AGGTCA) at 125/119 and a degenerated DR halfsite (ATGTTA) at 99/94 as sufficient and necessary for vegfD transcription. The vegfD DR element is bound and activated by the orphan receptors hepatocyte nuclear factor 4 alpha (HNF4 alpha) and chicken ovalbumin upstream promoter transcription factor (COUPTF)1/COUPTF2. Additionally, chromatin immunoprecipitation assays identified transcriptional coactivators cyclic AMPresponsive element binding proteinbinding protein and glucocorticoid receptor interacting protein 1 at the vegfD DR element and functional assays confirmed their stimulatory effect on the vegfD promoter. Histone deacetylase inhibition by trichostatin A led to accumulation of acetylated histones H3/H4 at the vegfD promoter, upregulation of vegfD mRNA levels, and transactivation of vegfD promoter reporter gene constructs in cancer cell lines. This study for the first time describes the molecular determinants in cis and trans controlling vegfD gene transcription and identifies interaction of HNF4 alpha and COUPTF1/COUPTF2 with a proximal, atypical DR element as indispensable for vegfD transcription. Moreover, our findings suggest that epigenetic control of histone acetylation represents an important determinant of vegfD gene expression in cancer cells. These results provide novel insights into the molecular machinery controlling vegfD gene expression and may add to a better understanding of the regulation of lymphangiogenesis in vascular development and cancer. http://www.ncbi.nlm.nih.gov/pubmed/18199540 Mon, 31 Dec 2007 00:00:00 -0800 The temporal and spatial regulation of gene expression in mammalian development is linked to the establishment of functional chromatin domains. Here, we report that tissuespecific transcription of a retrotransposon repeat in the murine growth hormone locus is required for gene activation. This repeat serves as a boundary to block the influence of repressive chromatin modifications. The repeat element is able to generate short, overlapping Pol IIand Pol IIIdriven transcripts, both of which are necessary and sufficient to enable a restructuring of the regulated locus into nuclear compartments. These data suggest that transcription of interspersed repetitive sequences may represent a developmental strategy for the establishment of functionally distinct domains within the mammalian genome to control gene activation. http://www.ncbi.nlm.nih.gov/pubmed/17626886 Sat, 30 Jun 2007 00:00:00 -0700 Multiple enzymatic activities are required for transcriptional initiation. The enzyme DNA topoisomerase II associates with gene promoter regions and can generate breaks in doublestranded DNA (dsDNA). Therefore, it is of interest to know whether this enzyme is critical for regulated gene activation. We report that the signaldependent activation of gene transcription by nuclear receptors and other classes of DNA binding transcription factors, including activating protein 1, requires DNA topoisomerase IIbetadependent, transient, sitespecific dsDNA break formation. Subsequent to the break, poly(adenosine diphosphateribose) polymerase1 enzymatic activity is induced, which is required for a nucleosomespecific histone H1highmobility group B exchange event and for local changes of chromatin architecture. Our data mechanistically link DNA topoisomerase IIbetadependent dsDNA breaks and the components of the DNA damage and repair machinery in regulated gene transcription. http://www.ncbi.nlm.nih.gov/pubmed/16794079 Wed, 31 May 2006 00:00:00 -0700 A decade of intensive investigation of coactivators and corepressors required for regulated actions of DNAbinding transcription factors has revealed a network of sequentially exchanged cofactor complexes that execute a series of enzymatic modifications required for regulated gene expression. These coregulator complexes possess "sensing" activities required for interpretation of multiple signaling pathways. In this review, we examine recent progress in understanding the functional consequences of "molecular sensor" and "molecular adaptor" actions of corepressor/coactivator complexes in integrating signaldependent programs of transcriptional responses at the molecular level. This strategy imposes a temporal order for modifying programs of transcriptional regulation in response to the cellular milieu, which is used to mediate developmental/homeostatic and pathological events. http://www.ncbi.nlm.nih.gov/pubmed/16751179 Wed, 31 May 2006 00:00:00 -0700 Epigenetic strategies control the orderly acquisition and maintenance of neuronal traits. A complex network of transcriptional repressors and corepressors mediates gene specificity for these strategies. In this issue of Cell, a study by Ballas and coworkers (Ballas et al., 2005) provides insight into the early lineage commitment events during neurogenesis. This study demonstrates that regulation of the REST/NRSF transcriptional repressor plays a fundamental role in the progression of pluripotent cells to lineagerestricted neural progenitors. http://www.ncbi.nlm.nih.gov/pubmed/15907461 Sat, 30 Apr 2005 00:00:00 -0700 Despite a genetic homogeneity, cells in multicellular organisms are structurally and functionally heterogeneous. The diversity of cell phenotypes exists due to differential transcriptional programs precisely regulated by specific nuclear factors and induced upon differentiation. The differences in gene expression programs arise during development and become heritable during cell proliferation. Over the last few years, research has focused on three molecular mechanisms that mediate epigenetic phenomena: DNA methylation, histone modification, and formation of specialized nuclear domains or territories. All of these processes are dynamic and tightly linked to the organism's development. Here we review advances in understanding the significance of epigenetic mechanisms in the establishment and maintenance of the specialized transcriptional program. We project the accumulated knowledge onto the delineation of the molecular mechanisms by which central nervous systemspecific genes are expressed in the nervous system and repressed in other tissues. http://www.ncbi.nlm.nih.gov/pubmed/15153425 Fri, 30 Apr 2004 00:00:00 -0700 A modified version of the chromosomal immunoprecipitation (ChIP) assay was implemented for discrete isolation and characterization of actively transcribed genes. Specifically, it was demonstrated with the gene II/91 of Sciara coprophila as a model locus that significant enhancement in the isolation of actively transcribed versus repressed and inactive genes can be achieved through the ChIP methodology. A combination of solidphase magnetic bead technology with chromosomal immunoprecipitation using antibodies that recognize the large subunit (c) of RNA polymerase II resulted in efficient isolation of the promoter region of gene II/91 exclusively during the amplification stage of larval development, when the gene is actively transcribed. It is postulated that the novel technology described herein can be applied to a wide variety of systems for efficient isolation and in vivo assessment of actively transcribed genes regulated by virtually any given transcription factor. http://www.ncbi.nlm.nih.gov/pubmed/12624958 Fri, 28 Feb 2003 00:00:00 -0800 The molecular mechanisms by which central nervous systemspecific genes are expressed only in the nervous system and repressed in other tissues remain a central issue in developmental and regulatory biology. Here, we report that the zincfinger genespecific repressor element RE1 silencing transcription factor/neuronal restricted silencing factor (REST/NRSF) can mediate extraneuronal restriction by imposing either active repression via histone deacetylase recruitment or longterm gene silencing using a distinct functional complex. Silencing of neuronalspecific genes requires the recruitment of an associated corepressor, CoREST, that serves as a functional molecular beacon for the recruitment of molecular machinery that imposes silencing across a chromosomal interval, including transcriptional units that do not themselves contain REST/NRSF response elements. http://www.ncbi.nlm.nih.gov/pubmed/12399542 Sat, 30 Nov 2002 00:00:00 -0800 Direct target loci for the transcription factor p53 were identified through the employment of a combination of a modified version of chromosomal immunoprecipitation and inverse PCR. Irradiation of Hela cells to drive DNA damage response was followed by sequential chromosomal immunoprecipitation utilizing antibodies which recognize the large subunit of RNA polymerase II and p53. Inverse PCR with degenerate oligonucleotides specific for the p53 binding site was subsequently performed on immunoprecipitated DNA and fragments containing putative p53 target genes were subcloned and sequenced. Two sequences were identified which contain nearconsensus p53 binding sites as well as recognition sites for the core transcriptional machinery including RNA polymerase II and Sp1. Cotransfections of vectors containing these sequences linked to a reporter with p53 expression vectors resulted in stimulation of transcription. Application of the technology described herein may result in the identification of target loci for a wide variety of transcription factors. http://www.ncbi.nlm.nih.gov/pubmed/12500542 Sat, 30 Nov 2002 00:00:00 -0800 Developmentally regulated initiation of DNA synthesis was studied in the fly Sciara at locus II/9A. PCR analysis of nascent strands revealed an initiation zone that spans approximately 8 kb in mitotic embryonic cells and endoreplicating salivary glands but contracts to 1.2 to 2.0 kb during DNA amplification of DNA puff II/9A. Thus, the amplification origin occurs within the initiation zone used for normal replication. The initiation zone lefthand border is constant, but the righthand border changes during development. Also, there is a shift in the preferred site for initiation of DNA synthesis during DNA amplification compared to that in preamplification stages. This is the first demonstration that once an initiation zone is defined in embryos, its borders and preferred replication start sites can change during development. Chromatin immunoprecipitation showed that the RNA polymerase II 140kDa subunit occupies the promoter of gene II/91 during DNA amplification, even though intense transcription will not start until the next developmental stage. RNA polymerase II is adjacent to the righthand border of the initiation zone at DNA amplification but not at preamplification, suggesting that it may influence the position of this border. These findings support a relationship between the transcriptional machinery and establishment of the replication initiation zone. http://www.ncbi.nlm.nih.gov/pubmed/12446763 Thu, 31 Oct 2002 00:00:00 -0800 Many common morphogenic, signaling and transcriptional hierarchy themes exist with respect to a number of different model systems representing mammalian organogenesis. The developing pituitary gland defines a fundamentally ideal system for the study and classification of biochemical and molecular events associated with biological transitions such as organ and cellular positional determination as well as lineagespecific terminal differentiation. Recent advances in defining the extrinsic and intrinsic biological cascades behind pituitary development have shed light on the crosstalk between signaling molecules and transcription factors as well as the combinatorial regulatory codes guiding gland maturation. A thorough assessment of these codes is critical to a comprehensive understanding of pituitary organogenesis and the mechanisms which may go awry during tumorigenesis. http://www.ncbi.nlm.nih.gov/pubmed/12200158 Wed, 31 Jul 2002 00:00:00 -0700 Defining the molecular mechanisms that coordinately regulate proliferation and differentiation is a central issue in development. Here, we describe a mechanism in which induction of the Ets repressor METS/PE1 links terminal differentiation to cell cycle arrest. Using macrophages as a model, we provide evidence that METS/PE1 blocks Rasdependent proliferation without inhibiting Rasdependent expression of cell typespecific genes by selectively replacing Ets activators on the promoters of cell cycle control genes. Antiproliferative effects of METS require its interaction with DP103, a DEAD boxcontaining protein that assembles a novel corepressor complex. Functional interactions between the METS/DP103 complex and E2F/ pRB family proteins are also necessary for inhibition of cellular proliferation, suggesting a combinatorial code that directs permanent cell cycle exit during terminal differentiation. http://www.ncbi.nlm.nih.gov/pubmed/12007404 Tue, 30 Apr 2002 00:00:00 -0700 Reciprocal gene activation and restriction during cell type differentiation from a common lineage is a hallmark of mammalian organogenesis. A key question, then, is whether a critical transcriptional activator of cell typespecific gene targets can also restrict expression of the same genes in other cell types. Here, we show that whereas the pituitaryspecific POU domain factor Pit1 activates growth hormone gene expression in one cell type, the somatotrope, it restricts its expression from a second cell type, the lactotrope. This distinction depends on a twobase pair spacing in accommodation of the bipartite POU domains on a conserved growth hormone promoter site. The allosteric effect on Pit1, in combination with other DNA binding factors, results in the recruitment of a corepressor complex, including nuclear receptor corepressor NCoR, which, unexpectedly, is required for active longterm repression of the growth hormone gene in lactotropes. http://www.ncbi.nlm.nih.gov/pubmed/11073444 Tue, 31 Oct 2000 00:00:00 -0800 Transcriptional repression plays crucial roles in diverse aspects of metazoan development, implying critical regulatory roles for corepressors such as NCoR and SMRT. Altered patterns of transcription in tissues and cells derived from NCoR genedeleted mice and the resulting block at specific points in CNS, erythrocyte, and thymocyte development indicated that NCoR was a required component of shortterm active repression by nuclear receptors and MAD and of a subset of longterm repression events mediated by REST/NRSF. Unexpectedly, NCoR and a specific deacetylase were also required for transcriptional activation of one class of retinoic acid response element. Together, these findings suggest that specific combinations of corepressors and histone deacetylases mediate the genespecific actions of DNAbound repressors in development of multiple organ systems. http://www.ncbi.nlm.nih.gov/pubmed/11030619 Thu, 31 Aug 2000 00:00:00 -0700 http://www.ncbi.nlm.nih.gov/pubmed/8724772 Mon, 30 Sep 1996 00:00:00 -0700