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BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates
epicardial activity during heart development and disease
#MMPMID28737171
Vieira JM
; Howard S
; Villa Del Campo C
; Bollini S
; Dubé KN
; Masters M
; Barnette DN
; Rohling M
; Sun X
; Hankins LE
; Gavriouchkina D
; Williams R
; Metzger D
; Chambon P
; Sauka-Spengler T
; Davies B
; Riley PR
Nat Commun
2017[Jul]; 8
(?): 16034
PMID28737171
show ga
Epicardium-derived cells (EPDCs) contribute cardiovascular cell types during
development and in adulthood respond to Thymosin ?4 (T?4) 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 T?4 and is recruited by CCAAT/enhancer-binding protein ? (C/EBP?)
to discrete regulatory elements in the Wt1 locus. BRG1-T?4 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.
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