Targeting P300/CBP reveals discrete regulation of transcription and chromatin accessibility by histone acetylation [ChIPseq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA727000 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14408500.fastq.gz | Fastqsanger.gz | |||
| SRR14408501.fastq.gz | Fastqsanger.gz | |||
| SRR14408502.fastq.gz | Fastqsanger.gz | |||
| SRR14408503.fastq.gz | Fastqsanger.gz | |||
| SRR14408504.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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