Journal article
Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition
Simon J Hogg, Olga Motorna, Leonie A Cluse, Timothy M Johanson, Hannah D Coughlan, Ramya Raviram, Robert M Myers, Matteo Costacurta, Izabela Todorovski, Lizzy Pijpers, Stefan Bjelosevic, Tobias Williams, Shannon N Huskins, Conor J Kearney, Jennifer R Devlin, Zheng Fan, Jafar S Jabbari, Ben P Martin, Mohamed Fareh, Madison J Kelly Show all
MOLECULAR CELL | CELL PRESS | Published : 2021
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..
View full abstractGrants
Awarded by National Health and Medical Research Council of Australia (NHMRC)
Awarded by National Institutes of Health (NIH)
Awarded by Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH
Awarded by National Cancer Institute (NCI) Cancer Center Support Grant (CCSG)
Funding Acknowledgements
The Peter MacCallum Foundation and Australian Cancer Research Foundation provide generous support for equipment and core facilities. S.J. Hogg was supported by the Cancer Council of Victoria (CCV), a National Health and Medical Research Council of Australia (NHMRC) Investigator Grant, and a Haematology Society of Australia & New Zealand (HSANZ) Educational Grant. R.W.J. was supported by the CCV, the NHMRC, and The Kids' Cancer Project. S.J.V. was supported by a Rubicon fellowship (Nederlandse Organisatie voor Wetenschappelijk Onderzoek [NWO]), an NHMRC Investigator Grant, and The Kids' Cancer Project. A.T.P., G.K.S., H.D.C., R.S.A., and T.M.J. received funding from the NHMRC (grants 1049307 and 1100451 to R.S.A. and T.M.J.; grant 1124081 to T.M.J.). J.D.L. was supported by National Institutes of Health (NIH) grant R01 CA 180475, a Specialized Center of Research Excellence grant from the Leukemia and Lymphoma Society (LLS), the Multiple Myeloma Research Foundation, and the Samuel Waxman Cancer Research Foundation. D.D.-R. was supported by an LLS Special Fellow Award. V.O.W. is supported by a Veski Innovation Fellowship, a Victorian Cancer Agency mid-career fellowship, and the NHMRC. J.S. is supported by a Medical Research Future Fund Clinician Researcher Fellowship. P.C.T. was supported by an NHMRC Project Grant (APP1161985), an NHMRC Career Development Fellowship (APP1109696), and an NHMRC Investigator Grant (APP1176417). R.M.M. is supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH under award T32GM007739 to the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program. Weacknowledge the use of the Integrated Genomics Operation Core, funded by the National Cancer Institute (NCI) Cancer Center Support Grant (CCSG; P30 CA08748), Cycle for Survival, and the Marie-Josee and Henry R. Kravis Center for Molecular Oncology.