2. Academic Validation
  3. Global identification of SWI/SNF targets reveals compensation by EP400

Global identification of SWI/SNF targets reveals compensation by EP400

  • Cell. 2023 Oct 29:S0092-8674(23)01088-7. doi: 10.1016/j.cell.2023.10.006.
Benjamin J E Martin 1,  Eileen F Ablondi 2,  Christine Goglia 2,  Claudia A Mimoso 2,  Piero R Espinel-Cabrera 2,  Karen Adelman 3
Affiliations

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: [email protected].
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.

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