The histone reader PHF7 cooperates with the SWI/SNF complex at cardiac super-enhancers to promote direct cardiac reprogramming

Direct cardiac reprogramming of fibroblasts to cardiomyocytes presents an attractive therapeutic strategy to restore cardiac function following injury. Cardiac reprogramming was initially achieved through the overexpression of the transcription factors Gata4, Mef2c, and Tbx5 (GMT), and later, Hand2 (GHMT) and Akt1 (AGHMT) were found to further enhance this process. Yet, staunch epigenetic barriers severely limit the ability of these cocktails to reprogram adult fibroblasts. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the histone reader PHF7 as the most potent activating factor. Mechanistically, PHF7 localizes to cardiac super-enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, increases chromatin accessibility and transcription factor binding at these sites. Importantly, PHF7 is the first epigenetic factor found to achieve efficient reprogramming in the absence of Gata4. Here, we highlight the underexplored necessity of cardiac epigenetic modifiers, such as PHF7, in harnessing chromatin remodeling complexes to overcome critical barriers to direct cardiac reprogramming. To understand the mechanism of PHF7 in reprogramming, we profiled the binding sites of PHF7 through PHF7 ChIP-Seq in day 2 iCLM MEFs both on its own (PHF7) and in the context of reprogramming (5F+PHF7). We further profiled chromatin accessibility through ATAC-Seq in day 2 iCLM MEFs in AGHMT (5F) and AGHMT+PHF7 (5F+PHF7) samples. Global changes in transcription were profiled by RNA-Seq in day 7 TTF iCLMs.