Journal
MOLECULAR CELL
Volume 81, Issue 10, Pages 2183-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2021.04.015
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Funding
- Cancer Council of Victoria (CCV)
- National Health and Medical Research Council of Australia (NHMRC) [1049307, 1100451, 1124081, APP1176417, APP1161985, APP1109696]
- Haematology Society of Australia & New Zealand (HSANZ) Educational Grant
- The Kids' Cancer Project
- Rubicon fellowship (Nederlandse Organisatie voor Wetenschappelijk Onderzoek [NWO])
- National Institutes of Health (NIH) [R01 CA 180475]
- Specialized Center of Research Excellence grant from the Leukemia and Lymphoma Society (LLS)
- Multiple Myeloma Research Foundation
- Samuel Waxman Cancer Research Foundation
- LLS Special Fellow Award
- Veski Innovation Fellowship
- Victorian Cancer Agency mid-career fellowship
- Medical Research Future Fund Clinician Researcher Fellowship
- Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH [T32GM007739]
- National Cancer Institute (NCI) Cancer Center Support Grant (CCSG) [P30 CA08748]
- Cycle for Survival
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- Peter MacCallum Foundation
- Australian Cancer Research Foundation
- National Health and Medical Research Council of Australia [1100451, 1124081] Funding Source: NHMRC
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The study found that catalytic inhibition of P300/CBP dynamically disrupts steady-state acetylation kinetics and suppresses oncogenic transcriptional networks without changing chromatin accessibility. CRISPR-Cas9 screening identified NCOR1 and HDAC3 as the key antagonists of P300/CBP by counteracting acetylation turnover kinetics. Deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, which can be therapeutically exploited by simultaneous KDM6A and 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 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 anticancer regimen.
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