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

Glynnis A. Garry, Svetlana Bezprozvannaya, Kenian Chen, Huanyu Zhou, Hisayuki Hashimoto, Maria Gabriela Morales, Ning Liu, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Direct cardiac reprogramming of fibroblasts to cardiomyocytes presents an attractive therapeutic strategy to restore cardiac function following injury. Cardiac reprogramming was initially achieved through overexpression of the transcription factors Gata4, Mef2c and Tbx5; later, Hand2 and Akt1 were found to further enhance this process1–5. Yet, staunch epigenetic barriers severely limit the ability of these cocktails to reprogramme adult fibroblasts6,7. 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 factor8. Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, it increases chromatin accessibility and transcription factor binding at these sites. Furthermore, PHF7 recruits cardiac transcription factors to activate a positive transcriptional autoregulatory circuit in reprogramming. Importantly, PHF7 achieves efficient reprogramming in the absence of Gata4. Here, we highlight the underexplored necessity of cardiac epigenetic readers, such as PHF7, in harnessing chromatin remodelling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.

Original languageEnglish (US)
Pages (from-to)467-475
Number of pages9
JournalNature cell biology
Volume23
Issue number5
DOIs
StatePublished - May 2021

ASJC Scopus subject areas

  • Cell Biology

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