Activation of Cardiac Enhancers and Inhibition of the Inflammatory Response Promotes Cardiac Reprogramming of Adult Fibroblasts. Mus musculus breed:C57BL/6

Direct reprogramming of fibroblasts to cardiomyocytes represents a potential means of restoring cardiac function following myocardial injury. We previously reported that addition of Akt in the presence of four cardiogenic transcription factors, Gata4, Hand2, Mef2c, and Tbx5 (AGHMT), efficiently activates the cardiac gene program in mouse embryonic fibroblasts but not in adult fibroblasts. To identify additional regulators of adult cardiac reprogramming, we carried out an unbiased screen of 1,052 open reading frame cDNAs encoding transcription factors and cytokines for those that could enhance or suppress the cardiogenic activity of AGHMT. This screen led to the discovery of 49 inducers and 129 repressors of cardiac reprogramming. We show that ZNF281 activates cardiac reprogramming by associating with GATA4 on cardiac enhancers and by inhibiting inflammatory signaling. These results identify ZNF281 as an efficient inducer of adult cardiac reprogramming and provide insights into the molecular mechanisms underlying the cardiac phenotype.