Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Chemical Biology Program, Harvard University, Cambridge, MA 02138, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cell. 2019 Nov 27;179(6):1342-1356.e23. doi: 10.1016/j.cell.2019.10.044. Epub 2019 Nov 20.
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.
哺乳动物的转换/蔗糖非发酵(mSWI/SNF)复合物是多组分机器,可重塑染色质结构。需要对亚基和结构域特异性对复合物活性的贡献进行剖析,以推进对机制的理解。在这里,我们研究了智力障碍疾病 Coffin-Siris 综合征(CSS)相关的、存在于多种癌症中的 SMARCB1(BAF47)亚基的假定卷曲螺旋 C 端结构域(CTD)中反复出现的单个残基突变的分子、结构和全基因组调控后果。我们发现,SMARCB1 CTD 包含一个碱性α螺旋,可直接与核小体酸性斑结合,而所有 CSS 相关突变均破坏了这种结合。此外,这些突变消除了 mSWI/SNF 介导的核小体重塑活性和增强子 DNA 可及性,而全基因组复合物定位没有变化。最后,杂合性 CSS 相关 SMARCB1 突变导致 iPSC 神经元分化过程中的显性基因调控和形态变化。这些研究揭示了 SMARCB1 CTD 的一个进化保守的结构作用,该作用在人类疾病中受到干扰。