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Cell. 2019 Nov 27;179(6):1342-1356.e23. doi: 10.1016/j.cell.2019.10.044. Epub 2019 Nov 20.

Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling.

Author information

1
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.
2
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.
3
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
4
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
5
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
6
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; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
8
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. Electronic address: cigall_kadoch@dfci.harvard.edu.

Abstract

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.

KEYWORDS:

ATP-dependent chromatin remodeling; BAF complex; Coffin-Siris syndrome; SMARCB1 (BAF47); chromatin accessibility; intellectual disability; mammalian SWI/SNF complexes; nucleosome acidic patch; nucleosome remodeling; structure

PMID:
31759698
DOI:
10.1016/j.cell.2019.10.044

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