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Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition
- Source :
- Mol Cell
- Publication Year :
- 2020
-
Abstract
- To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in hematological malignancies. We found that catalytic P300/CBP inhibition dynamically perturbs steady-state acetylation kinetics and suppresses oncogenic transcriptional networks in the absence of changes to chromatin accessibility. CRISPR-Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principal 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/CBP 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.
- Subjects :
- Transcription, Genetic
P300-CBP Transcription Factors
Methylation
Models, Biological
Histone Deacetylases
Article
Cell Line
Evolution, Molecular
Histones
03 medical and health sciences
0302 clinical medicine
Histone methylation
Humans
Gene Regulatory Networks
p300-CBP Transcription Factors
Epigenetics
Molecular Biology
Conserved Sequence
030304 developmental biology
Epigenomics
0303 health sciences
Genome
biology
Acetylation
Cell Biology
Oncogenes
Chromatin
Cell biology
Kinetics
Histone
biology.protein
Biocatalysis
Histone deacetylase
RNA Polymerase II
Co-Repressor Proteins
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 10974164
- Volume :
- 81
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Molecular cell
- Accession number :
- edsair.doi.dedup.....656c92ad303a7a22c45e2d1bca648c4a