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69
A bivalent chromatin structure marks key developmental genes in embryonic stem cells, Cell 125
, 2006
"... The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by ex ..."
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The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed ‘‘bivalent domains,’ ’ consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.
Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome.
- Nat. Genet.,
, 2007
"... Eukaryotic gene transcription is accompanied by acetylation and methylation of nucleosomes near promoters, but the locations and roles of histone modifications elsewhere in the genome remain unclear. We determined the chromatin modification states in high resolution along 30 Mb of the human genome ..."
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Cited by 202 (3 self)
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Eukaryotic gene transcription is accompanied by acetylation and methylation of nucleosomes near promoters, but the locations and roles of histone modifications elsewhere in the genome remain unclear. We determined the chromatin modification states in high resolution along 30 Mb of the human genome and found that active promoters are marked by trimethylation of Lys4 of histone H3 (H3K4), whereas enhancers are marked by monomethylation, but not trimethylation, of H3K4. We developed computational algorithms using these distinct chromatin signatures to identify new regulatory elements, predicting over 200 promoters and 400 enhancers within the 30-Mb region. This approach accurately predicted the location and function of independently identified regulatory elements with high sensitivity and specificity and uncovered a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2). Our results give insight into the connections between chromatin modifications and transcriptional regulatory activity and provide a new tool for the functional annotation of the human genome. Activation of eukaryotic gene transcription involves the coordination of a multitude of transcription factors and cofactors on regulatory DNA sequences such as promoters and enhancers and on the chromatin structure containing these elements 1-3 . Promoters are located at the 5¢ ends of genes immediately surrounding the transcriptional start site (TSS) and serve as the point of assembly of the transcriptional machinery and initiation of transcription 4 . Enhancers contribute to the activation of their target genes from positions upstream, downstream or within a target or neighboring gene Recent investigations using chromatin immunoprecipitation (ChIP) and microarray (ChIP-chip) experiments have described the chromatin architecture of transcriptional promoters in yeast, fly and mammalian systems 9 . In a manner largely conserved across species, active promoters are marked by acetylation of various residues of histones H3 and H4 and methylation of H3K4, particularly trimethylation of this residue. Nucleosome depletion is also a general characteristic of active promoters in yeast and flies, although this feature remains to be thoroughly examined in mammalian systems. Although some studies suggest that distal regulatory elements like enhancers may be marked by similar histone modification patterns 10-13 , the distinguishing chromatin features of promoters and enhancers have yet to be determined, hindering our understanding of a predictive histone code for different classes of regulatory elements. Here, we present high-resolution maps of multiple histone modifications and transcriptional regulators in 30 Mb of the human genome, demonstrating that active promoters and enhancers are associated with distinct chromatin signatures that can be used to predict these regulatory elements in the human genome. RESULTS Chromatin architecture and transcription factor localization We performed ChIP-chip analysis 14 to determine the chromatin architecture along 44 human loci selected by the ENCODE consortium as common targets for genomic analysis 15 , totaling 30 Mb.
Mapping of transcription factor binding regions in mammalian cells by ChIP: comparison of array- and sequencing-based technologies. Genome Res 17
, 2007
"... transcription factor binding regions Mapping of transcription factor (TF) binding regions has provided tremendous insight into our understanding of gene expression regulatory networks. Recent progress in this field can largely be credited to the application of chromatin immunoprecipitation (ChIP) te ..."
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Cited by 28 (3 self)
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transcription factor binding regions Mapping of transcription factor (TF) binding regions has provided tremendous insight into our understanding of gene expression regulatory networks. Recent progress in this field can largely be credited to the application of chromatin immunoprecipitation (ChIP) technologies. We compared strategies for mapping TF binding regions in mammalian cells using two different ChIP schemes: ChIP followed by DNA microarray analysis (ChIP-Chip) and ChIP followed by DNA sequencing (ChIP-PET). In these studies we first investigated parameters central to obtaining robust ChIP-chip datasets through the analysis of STAT1 targets in the ENCODE-designated regions of the human genome, and then compared ChIP-chip to ChIP-PET. We devised methods for scoring and comparing results among various tiling arrays and examined parameters such as DNA microarray format (oligonucleotide or PCR product elements), oligonucleotide length, hybridization conditions, and the use of competitor Cot-1 DNA to determine which among these variables enhances ChIP-chip performance in the detection of TF binding regions. The best performance was achieved with high density
Combinatorial analysis of transcription factor partners reveals recruitment of c-MYC to estrogen receptor �-responsive promoters
- Mol. Cell
, 2006
"... In breast cancer and normal estrogen target tissues, estrogen receptor-a (ERa) signaling results in the establishment of spatiotemporal patterns of gene expression. Whereas primary target gene regulation by ERa involves recruitment of coregulatory proteins, coactivators, or corepressors, activation ..."
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In breast cancer and normal estrogen target tissues, estrogen receptor-a (ERa) signaling results in the establishment of spatiotemporal patterns of gene expression. Whereas primary target gene regulation by ERa involves recruitment of coregulatory proteins, coactivators, or corepressors, activation of these downstream promoters by receptor signaling may also involve partnership of ERa with other transcription factors. By using an integrated, genome-wide approach that involves ChIP-chip and computational modeling, we uncovered 13 ERa-responsive promoters containing both ERa and c-MYC binding elements located within close proximity (13–214 bp) to each other. Estrogen stimulation enhanced the c-MYC-ERa interaction and facilitated the association of ERa, c-MYC, and the coactivator TRRAP with these estrogen-responsive promoters, resulting in chromatin remodeling and increased transcription. These results suggest that ERa and c-MYC physically interact to stabilize the ERa-coactivator complex, thereby permitting other signal transduction pathways to fine-tune estrogen-mediated signaling networks.
B: Next-generation genomics: an integrative approach
- Nat Rev Genet
"... Abstract | Integrating results from diverse experiments is an essential process in our effort to understand the logic of complex systems, such as development, homeostasis and responses to the environment. With the advent of high-throughput methodsincluding genome-wide association (GWA) studies, chr ..."
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Cited by 26 (1 self)
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Abstract | Integrating results from diverse experiments is an essential process in our effort to understand the logic of complex systems, such as development, homeostasis and responses to the environment. With the advent of high-throughput methodsincluding genome-wide association (GWA) studies, chromatin immunoprecipitation followed by sequencing (ChIP-seq) and RNA sequencing (RNA-seq) -acquisition of genome-scale data has never been easier. Epigenomics, transcriptomics, proteomics and genomics each provide an insightful, and yet one-dimensional, view of genome function; integrative analysis promises a unified, global view. However, the large amount of information and diverse technology platforms pose multiple challenges for data access and processing. This Review discusses emerging issues and strategies related to data integration in the era of next-generation genomics.
CpG islands - ‘a rough guide
- FEBS Lett
"... a b s t r a c t Mammalian genomes are punctuated by DNA sequences containing an atypically high frequency of CpG sites termed CpG islands (CGIs). CGIs generally lack DNA methylation and associate with the majority of annotated gene promoters. Many studies, however, have identified examples of CGI m ..."
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Cited by 20 (0 self)
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a b s t r a c t Mammalian genomes are punctuated by DNA sequences containing an atypically high frequency of CpG sites termed CpG islands (CGIs). CGIs generally lack DNA methylation and associate with the majority of annotated gene promoters. Many studies, however, have identified examples of CGI methylation in malignant cells, leading to improper gene silencing. CGI methylation also occurs in normal tissues and is known to function in X-inactivation and genomic imprinting. More recently, differential methylation has been shown between tissues, suggesting a potential role in transcriptional regulation during cell specification. Many of these tissue-specific methylated CGIs localise to regions distal to promoters, the regulatory function of which remains to be determined.
Locuswide chromatin remodeling and enhanced androgen receptor-mediated transcription in recurrent prostate tumor cells
- Mol. Cell. Biol
, 2006
"... Supplemental material This article cites 47 articles, 19 of which can be accessed free at: ..."
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Cited by 13 (3 self)
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Supplemental material This article cites 47 articles, 19 of which can be accessed free at:
Transcription-coupled deposition of histone modifications during MHC
, 2006
"... class II gene activation ..."
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Histone and chromatin
- Cell Biol. 2003; 15:172–183. [PubMed: 12648673
"... Genome-wide prediction and analysis of human ..."
DNA methyltransferase 3b preferentially associates with condensed chromatin
- Nucleic Acids Res
, 2011
"... ABSTRACT In mammals, DNA methylation is catalyzed by DNA methyltransferases (DNMTs) encoded by Dnmt1, Dnmt3a and Dnmt3b. Since, the mechanisms of regulation of Dnmts are still largely unknown, the physical interaction between Dnmt3b and chromatin was investigated in vivo and in vitro. In embryonic ..."
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Cited by 4 (0 self)
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ABSTRACT In mammals, DNA methylation is catalyzed by DNA methyltransferases (DNMTs) encoded by Dnmt1, Dnmt3a and Dnmt3b. Since, the mechanisms of regulation of Dnmts are still largely unknown, the physical interaction between Dnmt3b and chromatin was investigated in vivo and in vitro. In embryonic stem cell nuclei, Dnmt3b preferentially associated with histone H1-containing heterochromatin without any significant enrichment of silent-specific histone methylation. Recombinant Dnmt3b preferentially associated with nucleosomal DNA rather than naked DNA. Incorporation of histone H1 into nucleosomal arrays promoted the association of Dnmt3b with chromatin, whereas histone acetylation reduced Dnmt3b binding in vitro. In addition, Dnmt3b associated with histone deacetylase SirT1 in the nuclease resistant chromatin. These findings suggest that Dnmt3b is preferentially recruited into hypoacetylated and condensed chromatin. We propose that Dnmt3b is a 'reader' of higher-order chromatin structure leading to gene silencing through DNA methylation.
