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
  • 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: [email protected].
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.