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bioRxiv · 10.1101/2023.03.07.531379

Global Identification of Direct SWI/SNF Targets Reveals Compensation by EP400

Martin, B. J.·Ablondi, E. F.·Goglia, C.·Adelman, K.
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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 lung 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. Highlights- Genes repressed by long-term SWI/SNF loss do not accurately reflect direct targets - Promoters that fail to reestablish activity are those lacking a compensatory remodeler - Accessibility and activity recovery requires EP400, synthetically lethal with SWI/SNF - SWI/SNF dependence in cancer cells can be predicted from the promoter chromatin state

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Martin, B. J., Ablondi, E. F., Goglia, C., Adelman, K.. 2023-03-07. Global Identification of Direct SWI/SNF Targets Reveals Compensation by EP400. https://doi.org/10.1101/2023.03.07.531379

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