BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease.
Joaquim Miguel VieiraSara HowardCristina Villa Del CampoSveva BolliniKarina N DubéMegan MastersDamien N BarnetteMala RohlingXin SunLaura E HankinsDaria GavriouchkinaRuth WilliamsDaniel MetzgerPierre ChambonTatjana Sauka-SpenglerBenjamin DaviesPaul R RileyPublished in: Nature communications (2017)
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.
Keyphrases
- genome wide
- binding protein
- transcription factor
- single cell
- dna methylation
- genome wide identification
- smooth muscle
- copy number
- gene expression
- dna binding
- dna damage
- induced apoptosis
- coronary artery disease
- poor prognosis
- coronary artery
- left ventricular
- randomized controlled trial
- oxidative stress
- clinical trial
- cell proliferation
- cell death
- diabetic retinopathy
- cell cycle arrest
- vascular endothelial growth factor
- endothelial cells
- endoplasmic reticulum stress
- heat shock
- heat shock protein