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46
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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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.
A profile of histone lysine methylation across transcribed mammalian chromatin
- Mol. Cell Biol
, 2006
"... This article cites 79 articles, 31 of which can be accessed free ..."
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This article cites 79 articles, 31 of which can be accessed free
Structural Basis for the Specific Recognition of Methylated Histone H3 Lysine 4 by the WD-40 Protein WDR5 Short Article
"... The WD40 repeat protein WDR5 specifically associates with the K4-methylated histone H3 in human cells. To investigate the structural basis for this specific recognition, we have determined the structure of WDR5 in complex with a dimethylated H3-K4 peptide at 1.9 A˚ resolution. Unlike the chromodomai ..."
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The WD40 repeat protein WDR5 specifically associates with the K4-methylated histone H3 in human cells. To investigate the structural basis for this specific recognition, we have determined the structure of WDR5 in complex with a dimethylated H3-K4 peptide at 1.9 A˚ resolution. Unlike the chromodomain that recognizes the methylated H3-K4 through a hydrophobic cage, the specificity of WDR5 for methylated H3-K4 is conferred by the nonconventional hydrogen bonds between the two z-methyl groups of the dimethylated Lys4 and the carboxylate oxygen of Glu322 in WDR5. The three amino acids Ala-Arg-Thr preceding Lys4 form most of the specific contacts with WDR5, with Ala1 forming intermolecular hydrogen bonds and salt bridges, and the side chain of Arg2 inserting into the central channel of WDR5. Both structural and biochemical studies presented here suggest another mode of recognition for the methylated histone tail.
The nucleosome assembly activity of NAP1 is enhanced by Alien
- Mol. Cell Biol
, 2007
"... These include: This article cites 42 articles, 19 of which can be accessed free at: ..."
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These include: This article cites 42 articles, 19 of which can be accessed free at:
Variation of the nuclear, subnuclear and chromosomal flavanol deposition in hemlock and
"... Abstract: Nuclei of hemlock (Tsuga canadensis and Tsuga canadensis var. nana) were investigated for the presence of flavanols. Histochemical staining with p-dimethylaminocinnamaldehyde proved to be a highly valuable method yielding a bright blue flavanol coloration for nuclei. There was a significan ..."
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Abstract: Nuclei of hemlock (Tsuga canadensis and Tsuga canadensis var. nana) were investigated for the presence of flavanols. Histochemical staining with p-dimethylaminocinnamaldehyde proved to be a highly valuable method yielding a bright blue flavanol coloration for nuclei. There was a significant variation in flavanol deposition (1) among nuclei, (2) at the subnuclear level and also (3) along the chromosomes during mitosis. The presence of flavanols in nucleoli could not be established probably because they were too small, measuring less than 1 µm in diameter. In contrast to Tsuga, the cells and nuclei of rootlets from rye (Secale cereale) were totally devoid of natural flavanols. However, externally added flavanols, catechin and epicatechin, were bound to the rye nuclei, while the rather large nucleoli failed to associate with the flavanols. The strong sink activity of nucleoplasm and chromosomes for flavanols in Tsuga and Secale indicates a process which is apparently widespread even in distantly related plant species. Variations in chromatin-associated flavanols could to some extent be induced by acetylation/deacetylation of histones, as confirmed in the present study by means of UV-VIS spectroscopic titrations of histone sulphate and chemically acetylated histone sulphate.
Regulation of the androgen receptor by SET9-mediated methylation
, 2010
"... The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors that plays a critical role in regulating expression of genes involved in prostate development and transformation. Upon hormone binding, the AR associates with numerous co-regulator proteins that re ..."
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The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors that plays a critical role in regulating expression of genes involved in prostate development and transformation. Upon hormone binding, the AR associates with numerous co-regulator proteins that regulate the activation status of target genes via flux to the post-translational modification status of histones and the receptor. Here we show that the AR interacts with and is directly methylated by the histone methyltransferase enzyme SET9. Methylation of the AR on lysine 632 is necessary for enhancing transcriptional activity of the receptor by facilitating both inter-domain communication between the N- and C-termini and recruitment to androgen-target genes. We also show that SET9 is pro-proliferative and antiapoptotic in prostate cancer cells and demonstrates up-regulated nuclear expression in prostate cancer tissue. In all, our date indicate a new mechanism of AR regulation that may be therapeutically exploitable for prostate cancer treatment.
T-Bet Dependent Removal of Sin3A-Histone Deacetylase Complexes at the Ifng Locus Drives Th1 Differentiation 1
, 2013
"... This article cites 52 articles, 24 of which you can access for free at: ..."
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This article cites 52 articles, 24 of which you can access for free at:
References
, 1994
"... Protein structure refinement based on paramagnetic NMR shifts: Applications to wild-type and mutant forms of cytochrome c ..."
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Protein structure refinement based on paramagnetic NMR shifts: Applications to wild-type and mutant forms of cytochrome c
through changes
, 2006
"... Activation of the chicken Ig-b locus by the collaboration of scattered regulatory regions ..."
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Activation of the chicken Ig-b locus by the collaboration of scattered regulatory regions
