Global identification of SWI/SNF targets reveals compensation by EP400.

Autor:	Martin BJE; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA., Ablondi EF; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Goglia C; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Mimoso CA; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Espinel-Cabrera PR; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Adelman K; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: karen_adelman@hms.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2023 Nov 22; Vol. 186 (24), pp. 5290-5307.e26. Date of Electronic Publication: 2023 Nov 02.
DOI:	10.1016/j.cell.2023.10.006
Abstrakt:	Mammalian SWI/SNF chromatin remodeling complexes move and evict nucleosomes at gene promoters and enhancers to modulate DNA access. Although SWI/SNF subunits are commonly mutated in disease, therapeutic options are limited by our inability to predict SWI/SNF gene targets and conflicting studies on functional significance. Here, we leverage a fast-acting inhibitor of SWI/SNF remodeling to elucidate direct targets and effects of SWI/SNF. Blocking SWI/SNF activity causes a rapid and global loss of chromatin accessibility and transcription. Whereas repression persists at most enhancers, we uncover a compensatory role for the EP400/TIP60 remodeler, which reestablishes accessibility at most promoters during prolonged loss of SWI/SNF. Indeed, we observe synthetic lethality between EP400 and SWI/SNF in cancer cell lines and human cancer patient data. Our data define a set of molecular genomic features that accurately predict gene sensitivity to SWI/SNF inhibition in diverse cancer cell lines, thereby improving the therapeutic potential of SWI/SNF inhibitors. Competing Interests: Declaration of interests K.A. is a consultant to Syros Pharmaceuticals and Odyssey Therapeutics, is on the SAB of CAMP4 Therapeutics, and received research funding from Novartis not related to this work. (Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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