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

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

  • Cell. 2019 Nov 27;179(6):1342-1356.e23. doi: 10.1016/j.cell.2019.10.044.
Alfredo M Valencia 1,  Clayton K Collings 2,  Hai T Dao 3,  Roodolph St Pierre 1,  Yung-Chih Cheng 4,  Junwei Huang 4,  Zhen-Yu Sun 5,  Hyuk-Soo Seo 5,  Nazar Mashtalir 2,  Dawn E Comstock 6,  Olubusayo Bolonduro 2,  Nicholas E Vangos 5,  Zoe C Yeoh 5,  Mary Kate Dornon 4,  Crystal Hermawan 4,  Lee Barrett 4,  Sirano Dhe-Paganon 7,  Clifford J Woolf 4,  Tom W Muir 3,  Cigall Kadoch 8
Affiliations

Affiliations

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

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