Open AccessBRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease
Author(s) -
Joaquim Miguel Vieira,
Sara Howard,
Cristina Villa del Campo,
Sveva Bollini,
Kari. Dubé,
Megan Masters,
Damien N. Barnette,
Mala Rohling,
Xin Sun,
Laura E Hankins,
Daria Gavriouchkina,
Ruth M. Williams,
Daniel Metzger,
Pierre Chambon,
Tatjana SaukaSpengler,
Benjamin Davies,
Paul R. Riley
Publication year - 2017
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms16034
Subject(s) - swi/snf , chromatin immunoprecipitation , chromatin , chromatin remodeling , enhancer , biology , transcription factor , microbiology and biotechnology , heart development , gene , chromatin structure remodeling (rsc) complex , cancer research , embryonic stem cell , gene expression , genetics , promoter
Epicardium-derived cells (EPDCs) contribute cardiovascular cell types during development and in adulthood respond to Thymosin β4 (Tβ4) and myocardial infarction (MI) by reactivating a fetal gene programme to promote neovascularization and cardiomyogenesis. The mechanism for epicardial gene (re-)activation remains elusive. Here we reveal that BRG1, the essential ATPase subunit of the SWI/SNF chromatin–remodelling complex, is required for expression of Wilms’ tumour 1 ( Wt1 ), fetal EPDC activation and subsequent differentiation into coronary smooth muscle, and restores Wt1 activity upon MI. BRG1 physically interacts with Tβ4 and is recruited by CCAAT/enhancer-binding protein β (C/EBPβ) to discrete regulatory elements in the Wt1 locus. BRG1-Tβ4 co-operative binding promotes optimal transcription of Wt1 as the master regulator of embryonic EPDCs. Moreover, chromatin immunoprecipitation-sequencing reveals BRG1 binding at further key loci suggesting SWI/SNF activity across the fetal epicardial gene programme. These findings reveal essential functions for chromatin–remodelling in the activation of EPDCs during cardiovascular development and repair.