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

• Published in: Cell 2019-11, Vol.179 (6), p.1342-1356.e23
• Main Authors: Valencia, Alfredo M., Collings, Clayton K., Dao, Hai T., St. Pierre, Roodolph, Cheng, Yung-Chih, Huang, Junwei, Sun, Zhen-Yu, Seo, Hyuk-Soo, Mashtalir, Nazar, Comstock, Dawn E., Bolonduro, Olubusayo, Vangos, Nicholas E., Yeoh, Zoe C., Dornon, Mary Kate, Hermawan, Crystal, Barrett, Lee, Dhe-Paganon, Sirano, Woolf, Clifford J., Muir, Tom W., Kadoch, Cigall
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; amino acid sequences; ATP-dependent chromatin remodeling; BAF complex; chromatin accessibility; Chromatin Assembly and Disassembly - genetics; Chromosomal Proteins, Non-Histone - metabolism; Coffin-Siris syndrome; DNA; dominant genes; Enhancer Elements, Genetic - genetics; Female; Genome, Human; HEK293 Cells; HeLa Cells; heterozygosity; Heterozygote; human diseases; Humans; intellectual disability; Male; mammalian SWI/SNF complexes; mammals; Models, Molecular; Mutant Proteins - chemistry; Mutant Proteins - metabolism; mutation; Mutation - genetics; neoplasms; nucleosome acidic patch; nucleosome remodeling; nucleosomes; Nucleosomes - metabolism; Protein Binding; Protein Domains; SMARCB1 (BAF47); SMARCB1 Protein - chemistry; SMARCB1 Protein - genetics; SMARCB1 Protein - metabolism; structure; sucrose; Transcription Factors - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.10.044

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. [Display omitted] •A conserved SMARCB1 C-terminal α helix binds the nucleosome acidic patch•Recurrent point mutations disrupt this interaction and mSWI/SNF nucleosome remodeling•The SMARCB1 CTD is dispensable for genome-wide BAF complex targeting•Heterozygous SMARCB1 mutations impede Ngn2-mediated neuronal differentiation The SMARCB1 C-terminal alpha-helical domain binds the nucleosome acidic patch and mediates mSWI/SNF chromatin remodeling.