期刊
CELL
卷 179, 期 6, 页码 1342-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2019.10.044
关键词
-
资金
- Howard Hughes Medical Institute Gilliam Fellowship Program
- NIH [5 T32 GM095450-04, R35NS105076, U54HD090255, 5R37 GM086868, P01 CA196539]
- Ford Foundation Fellowship
- NIH DP2 New Innovator Award [1DP2CA195762-01]
- American Cancer Society Research Scholar Award [RSG-14-051-01-DMC]
- Pew-Stewart Scholars in Cancer Research Grant
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 alpha 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据