CBP/P300 Dependent Histone H3K27 Acetylation
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB25006 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR2307860.fastq.gz | Fastqsanger.gz | |||
| ERR2307870.fastq.gz | Fastqsanger.gz | |||
| ERR2307880.fastq.gz | Fastqsanger.gz | |||
| ERR2307890.fastq.gz | Fastqsanger.gz | |||
| ERR2307900.fastq.gz | Fastqsanger.gz |
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Project description:Histone acetylation is important for the activation of gene transcription but little is known about its direct ‘read/write’ mechanisms. Here, we report cryo-electron microscopy structures in which a p300/CBP multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTac via the bromodomain pocket responsible for ‘reading’, but also interacted with the DNA minor grooves via the outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 ‘writes’ by ‘reading’ H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP ‘replicates’ histone NT acetylation within the H3-H4 tetramer to inherit epigenetic storage, and ‘transcribes’ it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.
2023-05-08 | PXD040835 | Pride
Project description:The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators; however, their acetylation targets, site-specific acetylation kinetics, and function in proteome regulation are incompletely understood. We combined quantitative proteomics with novel CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to show that CBP/p300 acetylates thousands of sites, including signature histone sites, as well as a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Kinetic analysis identified a subset of CBP/p300-regulated sites with very rapid (<30min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions, as well as for understanding the impact of small molecule inhibitors targeting its catalytic and bromodomain activities.
2018-06-10 | PXD005252 | Pride
Project description:Ectopic expression of the double homeodomain transcription factor DUX4 causes facioscapulohumeral muscular dystrophy (FSHD). Mechanisms of action of DUX4 are currently unknown. Using immortalized human myoblasts with a titratable DUX4 transgene, we identify by mass spectrometry an interaction between the DUX4 C-terminus and the histone acetyltransferases p300/CBP. Chromatin immunoprecipitation shows that DUX4 recruits p300 to its target gene, ZSCAN4, displaces histone H3 from the center of its binding site, and induces H3K27Ac in its vicinity, but C-terminal deleted DUX4 does not. We show that a DUX4 minigene, bearing only the homeodomains and C-terminus, is transcriptionally functional and cytotoxic, and that overexpression of a nuclear targeted C-terminus impairs the ability of WT DUX4 to interact with p300 and to regulate target genes. Genomic profiling of DUX4, histone H3, and H3 modifications reveals that DUX4 binds two classes of locus: DNase accessible H3K27Ac-rich chromatin and inaccessible H3K27Ac-depleted MaLR-enriched chromatin. At this latter class, it acts as a pioneer factor, recruiting H3K27 acetyltransferase activity and opening the locus for transcription. In concert with local increased H3K27Ac, the strong H3K27Ac peaks at distant sites are significantly depleted of H3K27Ac, thus DUX4 uses its C-terminus to induce a global reorganization of H3K27 acetylation. Two biological samples were analyzed with 4 antibodies for ChIP-Seq and in triplicate for RNA-Seq.
2016-03-10 | E-GEOD-78158 | biostudies-arrayexpress
Project description:The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators; however, their acetylation targets, site-specific acetylation kinetics, and function in proteome regulation are incompletely understood. We combined quantitative proteomics with novel CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to show that CBP/p300 acetylates thousands of sites, including signature histone sites, as well as a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Kinetic analysis identified a subset of CBP/p300-regulated sites with very rapid (<30min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions, as well as for understanding the impact of small molecule inhibitors targeting its catalytic and bromodomain activities.
| MSV000095981 | MassIVE
Project description:To test the long-standing paradigm directly linking histone acetylation with chromatin decompaction and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP. We discovered that P300/CBP inhibition dynamically perturbs acetylation kinetics and dramatically suppresses core-transcriptional networks in the absence of changes to chromatin accessibility. CRISPR/Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principle antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300 inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
2021-05-11 | GSE173811 | GEO
Project description:To test the long-standing paradigm directly linking histone acetylation with chromatin decompaction and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP. We discovered that P300/CBP inhibition dynamically perturbs acetylation kinetics and dramatically suppresses core-transcriptional networks in the absence of changes to chromatin accessibility. CRISPR/Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principle antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300 inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
2021-05-11 | GSE173775 | GEO
Project description:To test the long-standing paradigm directly linking histone acetylation with chromatin decompaction and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP. We discovered that P300/CBP inhibition dynamically perturbs acetylation kinetics and dramatically suppresses core-transcriptional networks in the absence of changes to chromatin accessibility. CRISPR/Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principle antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300 inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
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Project description:To test the long-standing paradigm directly linking histone acetylation with chromatin decompaction and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP. We discovered that P300/CBP inhibition dynamically perturbs acetylation kinetics and dramatically suppresses core-transcriptional networks in the absence of changes to chromatin accessibility. CRISPR/Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principle antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300 inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
2021-05-11 | GSE174272 | GEO
Project description:To test the long-standing paradigm directly linking histone acetylation with chromatin decompaction and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP. We discovered that P300/CBP inhibition dynamically perturbs acetylation kinetics and dramatically suppresses core-transcriptional networks in the absence of changes to chromatin accessibility. CRISPR/Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principle antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300 inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
2021-05-11 | GSE174267 | GEO
Project description:To test the long-standing paradigm directly linking histone acetylation with chromatin decompaction and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP. We discovered that P300/CBP inhibition dynamically perturbs acetylation kinetics and dramatically suppresses core-transcriptional networks in the absence of changes to chromatin accessibility. CRISPR/Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principle antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300 inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
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