Global identification of SWI/SNF targets reveals compensation by EP400

Benjamin J E Martin; Eileen F Ablondi; Christine Goglia; Claudia A Mimoso; Piero R Espinel-Cabrera; Karen Adelman

doi:10.1016/j.cell.2023.10.006

Global identification of SWI/SNF targets reveals compensation by EP400

Cell. 2023 Nov 22;186(24):5290-5307.e26. doi: 10.1016/j.cell.2023.10.006. Epub 2023 Nov 2.

Authors

Benjamin J E Martin¹, Eileen F Ablondi², Christine Goglia², Claudia A Mimoso², Piero R Espinel-Cabrera², Karen Adelman³

Affiliations

¹ Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA.
² Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
³ 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.

PMID: 37922899
DOI: 10.1016/j.cell.2023.10.006

Abstract

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.

Keywords: BRG1; EP400; PRO-seq; RNAPII; SWI/SNF; chromatin accessibility; chromatin remodeling; combination therapies; epigenetic regulators; transcription.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chromatin
Chromatin Assembly and Disassembly
Humans
Mice
Nuclear Proteins* / metabolism
Nucleosomes
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Chromatin
Nuclear Proteins
Nucleosomes
Transcription Factors
Ep400 protein, mouse