SWI-SNF-like fetal gene reprogramming dynamically regulates epicardial progenitor activity

Epicardium-derived cells (EPDCs) contribute cardiac cell types during development and in adulthood respond to Thymosin β4 (Tβ4) and myocardial infarction (MI) by reactivating a fetal gene program to promote neovascularization and cardiomyogenesis. The mechanism for epicardial gene activation remains elusive. Here we reveal that SWI/SNF chromatin-remodeling complexes restored embryonic potential upon MI. BRG1, the essential ATPase subunit of SWI/SNF, physically interacted with Tβ4 and was recruited by CCAAT/enhancer-binding protein β (C/EBPβ) to discrete regulatory elements in the Wilm’s tumor 1 (Wt1) locus. BRG1-Tβ4 co-operative binding promoted transcription of Wt1 as the master regulator of embryonic EPDCs and Wt1as, an antisense lncRNA produced from within intron 1, which increased Wt1 mRNA stability through heteroduplex formation. ChIP-seq revealed global BRG1 binding which was enhanced by Tβ4 at key embryonic epicardial loci downstream of Wt1. These findings reveal novel essential functions for chromatin-remodeling and antisense RNA in the embryonic programming of EPDCs during cardiac development and repair.