biostudies-literatureHogg SJEuropean Hematology AssociationNCI NIH HHSNational Health and Medical Research CouncilNational Institutes of HealthNIGMS NIH HHS2183-2200.e13https://www.ebi.ac.uk/biostudies/studies/S-EPMC8183601biostudies-literatureUnknown81(10)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 concMolecular cellTargeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition.PMC8183601T32 GM007739P30 CA008748R01 CA180475TRTH180Coughlan HDFeran BKhong TDevlin JRKearney CJLai AHarrison SJCluse LALicht JDDupere-Richer DAllan RSHuskins SNJabbari JSHogg SJTaberlay PCMotorna OJohanson TMBromberg KDKelly MJBjelosevic SAbdel-Wahab OMyers RMCostacurta MSmyth GKPijpers LFan ZPapenfuss ATMartin BPVervoort SJJohnstone RWTodorovski ISpencer ASandow JJShortt JRaviram RWebb AIFareh MWilliams TWickramasinghe VOGregory GKnight DLandau DAfalseTargeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition.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 conc2021-01-01T00:00:00Z2021 May2026-05-31T07:09:58.41Z2025-04-04T07:57:41.776ZS-EPMC81836013401978810.1016/j.molcel.2021.04.015