Mammalian switch/sucrose non-fermentable (mSWI/SNF) complexes are multi-component machines that remodel chromatin architecture. Dissection of the subunit- and domain-specific contributions to complex activities is needed to advance mechanistic understanding. Here, we examine the molecular, structural, and genome-wide regulatory consequences of recurrent, single-residue mutations in the putative coiled-coil C-terminal domain (CTD) of the SMARCB1 (BAF47) subunit, which cause the intellectual disability disorder Coffin-Siris syndrome (CSS), and are recurrently found in cancers. We find that the SMARCB1 CTD contains a basic α helix that binds directly to the nucleosome acidic patch and that all CSS-associated mutations disrupt this binding. Furthermore, these mutations abrogate mSWI/SNF-mediated nucleosome remodeling activity and enhancer DNA accessibility without changes in genome-wide complex localization. Finally, heterozygous CSS-associated SMARCB1 mutations result in dominant gene regulatory and morphologic changes during iPSC-neuronal differentiation. These studies unmask an evolutionarily conserved structural role for the SMARCB1 CTD that is perturbed in human disease.

中文翻译：

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复发的SMARCB1突变揭示了增强mSWI / SNF复杂染色质重塑的核小体酸性补丁相互作用位点。

哺乳动物开关/蔗糖不可发酵（mSWI / SNF）复合物是重塑染色质结构的多组分机器。需要分解对复杂活动的亚单位和特定领域的贡献，以促进对机械的理解。在这里，我们研究了SMARCB1（BAF47）亚基的推定卷曲螺旋C末端结构域（CTD）中反复出现的单一残基突变的分子，结构和全基因组范围调节后果，该突变会导致智障儿童棺材-Siris综合征（CSS），经常在癌症中发现。我们发现SMARCB1 CTD包含一个直接与核小体酸性斑块直接结合的碱性α螺旋，并且所有与CSS相关的突变都破坏了这种结合。此外，这些突变消除了mSWI / SNF介导的核小体重塑活性和增强剂DNA可及性，而不会改变全基因组范围内的复杂定位。最后，杂合CSS相关的SMARCB1突变导致iPSC神经元分化过程中的主要基因调节和形态变化。这些研究揭示了在人类疾病中受到干扰的SMARCB1 CTD在进化上保守的结构作用。