Dr Joaquim Vieira : Epigenetic mechanisms of epicardial gene reactivation to repair the adult heart

Epicardium-derived cells (EPDCs) play an essential role during heart development by contributing to the major cardiovascular cell types: smooth muscle cells, interstitial fibroblasts, endothelial cells and cardiomyocytes. Critical to this process is the epicardially-expressed Wilms’ tumour 1 (Wt1) gene. The activity of EPDCs is significantly reduced during the later stages of embryogenesis leading to the characteristic quiescent phenotype of the adult epicardium. This gradual loss of activity can be followed by monitoring the expression of Wt1. Previously, we have shown that stimulation (priming) with the monomeric-actin binding peptide thymosin β4 (Tβ4) is capable of restoring the embryonic potential to the adult epicardium in vivo by, reactivating Wt1 and mobilising EPDCs to promote neovascularisation and de novo cardiomyogenesis following injury. However, the mechanism for Tβ4-mediated reactivation remains elusive.

Here, we report findings arising from an in vivo chromatin immunoprecipitation screen to map epigenetic changes mediated by SWI/SNF-chromatin remodelling complexes and histone post-translational modifications at the level of Wt1, both in the developing and adult (intact and injured) heart. In addition, we report the in vivo requirement for endogenous versus exogenous Tβ4 (priming) for the epigenetic reprogramming of the adult epicardium. In vitro and in vivo studies are on-going to further dissect out the Tβ4-mediated epigenetic mechanism of Wt1 reactivation. Understanding how to restore embryonic potential to adult EPDCs, following injury, may underpin the development of resident cell-based therapies for heart repair.