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

TitleRecurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling.
Publication TypeJournal Article
Year of Publication2019
AuthorsValencia, AM, Collings, CK, Dao, HT, St Pierre, R, Cheng, Y-C, Huang, J, Sun, Z-Y, Seo, H-S, Mashtalir, N, Comstock, DE, Bolonduro, O, Vangos, NE, Yeoh, ZC, Dornon, MKate, Hermawan, C, Barrett, L, Dhe-Paganon, S, Woolf, CJ, Muir, TW, Kadoch, C
Date Published2019 11 27
KeywordsAmino Acid Sequence, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Female, Genome, Human, HEK293 Cells, HeLa Cells, Heterozygote, Humans, Male, Models, Molecular, Mutant Proteins, Mutation, Nucleosomes, Protein Binding, Protein Domains, SMARCB1 Protein, Transcription Factors

<p>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.</p>

Alternate JournalCell
PubMed ID31759698
PubMed Central IDPMC7175411
Grant ListR35 NS105076 / NS / NINDS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
P01 CA196539 / CA / NCI NIH HHS / United States
T32 GM095450 / GM / NIGMS NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
DP2 CA195762 / CA / NCI NIH HHS / United States
R37 GM086868 / GM / NIGMS NIH HHS / United States