Mutation of SMARCA4 (BRG1), the ATPase of BAF (mSWI/SNF) and PBAF complexes, contributes to a range of malignancies and neurologic disorders. Unfortunately, the effects of SMARCA4 missense mutations have remained uncertain. Here we show that SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of remodeling. We find that heterozygous expression of mutants alters the open chromatin landscape at thousands of sites across the genome. Loss of DNA accessibility does not directly overlap with Polycomb accumulation, but is enriched in ‘A compartments’ at active enhancers, which lose H3K27ac but not H3K4me1. Affected positions include hundreds of sites identified as superenhancers in many tissues. Dominant-negative mutation induces pro-oncogenic expression changes, including increased expression of Myc and its target genes. Together, our data suggest that disruption of enhancer accessibility represents a key source of altered function in disorders with SMARCA4 mutations in a wide variety of tissues.

中文翻译：

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显性阴性 SMARCA4 突变体改变了组织无限制增强子的可及性景观

SMARCA4 ( BRG1 )、BAF 的 ATP 酶 (mSWI/SNF) 和 PBAF 复合物的突变导致一系列恶性肿瘤和神经系统疾病。不幸的是，SMARCA4错义突变的影响仍然不确定。在这里，我们展示了SMARCA4癌症错义突变靶向保守的ATP酶表面并破坏重塑的机械化学循环。我们发现突变体的杂合表达改变了基因组数千个位点的开放染色质景观。DNA 可及性的丧失不直接与 Polycomb 积累重叠，但在活性增强子的“A 隔间”中富集，失去 H3K27ac 而不是 H3K4me1。受影响的位置包括在许多组织中被确定为超增强子的数百个位点。显性阴性突变诱导促癌基因表达变化，包括Myc及其靶基因的表达增加。总之，我们的数据表明，增强子可及性的破坏是SMARCA4疾病功能改变的关键来源各种组织中的突变。