Global identification of SWI/SNF targets reveals compensation by EP400

• Published in: Cell 2023-11, Vol.186 (24), p.5290-5307.e26
• Main Authors: Martin, Benjamin J.E., Ablondi, Eileen F., Goglia, Christine, Mimoso, Claudia A., Espinel-Cabrera, Piero R., Adelman, Karen
• Format: Article
• Language: English
• Subjects: Animals; BRG1; Chromatin; chromatin accessibility; Chromatin Assembly and Disassembly; chromatin remodeling; combination therapies; EP400; epigenetic regulators; Humans; Mice; Nuclear Proteins - metabolism; Nucleosomes; PRO-seq; RNAPII; SWI/SNF; transcription; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2023.10.006

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. [Display omitted] •Genes repressed by long-term SWI/SNF loss do not accurately reflect direct targets•Compensatory remodeler EP400/TIP60 allows many promoters to recover accessibility•EP400 loss is synthetically lethal with perturbation of SWI/SNF•SWI/SNF dependence in cancer cells can be predicted from the promoter chromatin state Subunits of SWI/SNF chromatin remodeling complexes are often mutated in disease, but it has been difficult to predict gene sensitivity to SWI/SNF loss or inhibition. Time-resolved assays, however, reveal an initial global loss of chromatin accessibility and a mechanism of recovery at promoters following a regulatory logic dictated by the targeting of a compensatory remodeler, EP400.