Suppression of canonical TGF-β signaling enables GATA4 to interact with H3K27me3 demethylase JMJD3 to promote cardiomyogenesis

Andrew S. Riching, Etienne Danis, Yuanbiao Zhao, Yingqiong Cao, Congwu Chi, Rushita A. Bagchi, Brianna J. Klein, Hongyan Xu, Tatiana G. Kutateladze, Timothy A. McKinsey, Peter M. Buttrick, Kunhua Song

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Direct reprogramming of fibroblasts into cardiomyocytes (CMs) represents a promising strategy to regenerate CMs lost after ischemic heart injury. Overexpression of GATA4, HAND2, MEF2C, TBX5, miR-1, and miR-133 (GHMT2m) along with transforming growth factor beta (TGF-β) inhibition efficiently promote reprogramming. However, the mechanisms by which TGF-β blockade promotes cardiac reprogramming remain unknown. Here, we identify interactions between the histone H3 lysine 27 trimethylation (H3K27me3) demethylase JMJD3, the SWI/SNF remodeling complex subunit BRG1, and cardiac transcription factors. Furthermore, canonical TGF-β signaling regulates the interaction between GATA4 and JMJD3. TGF-β activation impairs the ability of GATA4 to bind target genes and prevents demethylation of H3K27 at cardiac gene promoters during cardiac reprogramming. Finally, a mutation in GATA4 (V267M) that is associated with congenital heart disease exhibits reduced binding to JMJD3 and impairs cardiomyogenesis. Thus, we have identified an epigenetic mechanism wherein canonical TGF-β pathway activation impairs cardiac gene programming, in part by interfering with GATA4-JMJD3 interactions.

Original languageEnglish (US)
Pages (from-to)44-59
Number of pages16
JournalJournal of molecular and cellular cardiology
StatePublished - Apr 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


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