Heterozygous Mutations in SMARCA2 Reprogram the Enhancer Landscape by Global Retargeting of SMARCA4.
Amino Acid Substitution
Cell Differentiation
/ genetics
Chromatin
/ genetics
DNA Helicases
/ genetics
Enhancer Elements, Genetic
Facies
Foot Deformities, Congenital
/ genetics
Fos-Related Antigen-2
/ biosynthesis
HEK293 Cells
Heterozygote
Human Embryonic Stem Cells
/ metabolism
Humans
Hypotrichosis
/ genetics
Intellectual Disability
/ genetics
Mutation, Missense
Neural Stem Cells
/ metabolism
Nuclear Proteins
/ genetics
SOXB1 Transcription Factors
/ genetics
Transcription Factors
/ genetics
AP-1
SMARCA2
SWI/SNF complex
chromatin remodeling
neural differentiation
neural progenitor cells
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
05 09 2019
05 09 2019
Historique:
received:
07
12
2018
revised:
24
04
2019
accepted:
18
06
2019
pubmed:
4
8
2019
medline:
30
1
2020
entrez:
4
8
2019
Statut:
ppublish
Résumé
Mammalian SWI/SNF complexes are multi-subunit chromatin remodeling complexes associated with an ATPase (either SMARCA4 or SMARCA2). Heterozygous mutations in the SMARCA2 ATPase cause Nicolaides-Baraitser syndrome (NCBRS), an intellectual disability syndrome associated with delayed speech onset. We engineered human embryonic stem cells (hESCs) to carry NCBRS-associated heterozygous SMARCA2 K755R or R1159Q mutations. While SMARCA2 mutant hESCs were phenotypically normal, differentiation to neural progenitors cells (NPCs) was severely impaired. We find that SMARCA2 mutations cause enhancer reorganization with loss of SOX3-dependent neural enhancers and prominent emergence of astrocyte-specific de novo enhancers. Changes in chromatin accessibility at enhancers were associated with an increase in SMARCA2 binding and retargeting of SMARCA4. We show that the AP-1 family member FRA2 is aberrantly overexpressed in SMARCA2 mutant NPCs, where it functions as a pioneer factor at de novo enhancers. Together, our results demonstrate that SMARCA2 mutations cause impaired differentiation through enhancer reprogramming via inappropriate targeting of SMARCA4.
Identifiants
pubmed: 31375262
pii: S1097-2765(19)30480-0
doi: 10.1016/j.molcel.2019.06.024
pmc: PMC7291823
mid: NIHMS1533064
pii:
doi:
Substances chimiques
Chromatin
0
FOSL2 protein, human
0
Fos-Related Antigen-2
0
Nuclear Proteins
0
SMARCA2 protein, human
0
SOX3 protein, human
0
SOXB1 Transcription Factors
0
Transcription Factors
0
SMARCA4 protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
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
891-904.e7Subventions
Organisme : NCI NIH HHS
ID : P30 CA014195
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA184043
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI151123
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM128943
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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