Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; Monash Haematology, Monash Health, Clayton, 3168, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton, 3800, Australia.
Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
New York Genome Center, New York, NY 10013, USA.
Tri-Institutional MD-PhD Program, Weill Cornell Medicine, Rockefeller University, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; RNA Biology and Cancer Laboratory, Peter MacCallum Cancer Centre, Melbourne, 3000, Australia.
Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, 7000, Australia.
Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Australia.
Division of Hematology/Oncology, The University of Florida Health Cancer Center, Gainesville, FL 32608, USA.
Australian Center for Blood Diseases, Monash University, Melbourne, 3004, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; Clinical Hematology, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Royal Melbourne Hospital, Melbourne, 3000, Australia.
Monash Haematology, Monash Health, Clayton, 3168, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton, 3800, Australia.
Discovery, Global Pharmaceutical Research and Development, AbbVie, North Chicago, IL 60064, USA.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; School of Mathematics and Statistics, The University of Melbourne, Parkville, 3010, Australia.
New York Genome Center, New York, NY 10013, USA; Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; Monash Haematology, Monash Health, Clayton, 3168, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton, 3800, Australia.
Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia. Electronic address: stephin.vervoort@petermac.org.
Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia. Electronic address: ricky.johnstone@petermac.org.
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.
