哺乳动物 SWI/SNF 染色质重塑复合物移动并驱逐基因启动子和增强子处的核小体，以调节 DNA 访问。尽管 SWI/SNF 亚基在疾病中通常会发生突变，但由于我们无法预测 SWI/SNF 基因靶点以及功能意义方面的研究相互矛盾，治疗选择受到限制。在这里，我们利用 SWI/SNF 重塑的速效抑制剂来阐明 SWI/SNF 的直接靶点和作用。阻断 SWI/SNF 活性会导致染色质可及性和转录迅速全面丧失。尽管抑制在大多数增强子中持续存在，但我们发现了 EP400/TIP60 重塑子的补偿作用，它在 SWI/SNF 长期丢失期间重建了大多数启动子的可及性。事实上，我们在癌细胞系和人类癌症患者数据中观察到 EP400 和 SWI/SNF 之间的综合致死率。我们的数据定义了一组分子基因组特征，可准确预测不同癌细胞系中对 SWI/SNF 抑制的基因敏感性，从而提高 SWI/SNF 抑制剂的治疗潜力。版权所有 © 2023 Elsevier Inc. 保留所有权利。

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.Copyright © 2023 Elsevier Inc. All rights reserved.