Metabolic and age-associated epigenetic barriers during direct reprogramming of mouse fibroblasts into induced cardiomyocytes

Heart disease is the leading cause of mortality in developed countries. Although conventional treatments exist, novel regenerative procedures are warranted for improving patients well fare. The use of direct cardiac conversion (DCC) of fibroblasts by the expression of the cardiogenic factors Mef2c, Gata4, and Tbx5 (MGT) can create induced cardiomyocytes (iCMs). Besides holding great promise, DCC lacks clinical effectiveness especially in adult cells, and the impact of metabolic and age-associated epigenetic barriers remains elusive. Here we demonstrate by histone PTMs analysis that DCC triggers major alterations in the epigenetic landscape, which differ with age. Moreover, we show that metabolic modulation in vitro and dietary manipulations in vivo that improves DCC efficiency are accompanied by significant alterations in the histone acetylation and methylation landscape