Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling.
Amino Acid Sequence
Chromatin Assembly and Disassembly
/ genetics
Chromosomal Proteins, Non-Histone
/ metabolism
Enhancer Elements, Genetic
/ genetics
Female
Genome, Human
HEK293 Cells
HeLa Cells
Heterozygote
Humans
Male
Models, Molecular
Mutant Proteins
/ chemistry
Mutation
/ genetics
Nucleosomes
/ metabolism
Protein Binding
Protein Domains
SMARCB1 Protein
/ chemistry
Transcription Factors
/ metabolism
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
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
27 11 2019
27 11 2019
Historique:
received:
17
05
2019
revised:
02
09
2019
accepted:
30
10
2019
pubmed:
25
11
2019
medline:
28
5
2020
entrez:
25
11
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31759698
pii: S0092-8674(19)31221-8
doi: 10.1016/j.cell.2019.10.044
pmc: PMC7175411
mid: NIHMS1545307
pii:
doi:
Substances chimiques
Chromosomal Proteins, Non-Histone
0
Mutant Proteins
0
Nucleosomes
0
SMARCB1 Protein
0
SMARCB1 protein, human
0
SWI-SNF-B chromatin-remodeling complex
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1342-1356.e23Subventions
Organisme : NINDS NIH HHS
ID : R35 NS105076
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA196539
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM095450
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090255
Pays : United States
Organisme : NCI NIH HHS
ID : DP2 CA195762
Pays : United States
Organisme : NIGMS NIH HHS
ID : R37 GM086868
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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