PT  - JOURNAL ARTICLE
AU  - Andrew S. Riching
AU  - Etienne Danis
AU  - Yuanbiao Zhao
AU  - Yingqiong Cao
AU  - Congwu Chi
AU  - Rushita A. Bagchi
AU  - Brianna J. Klein
AU  - Hongyan Xu
AU  - Tatiana G. Kutateladze
AU  - Timothy A. McKinsey
AU  - Peter M. Buttrick
AU  - Kunhua Song
TI  - Suppression of canonical TGF-β signaling enables GATA4 to interact with H3K27me3 demethylase JMJD3 to promote cardiomyogenesis
AID  - 10.1101/2020.02.12.945790
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.12.945790
4099  - http://biorxiv.org/content/early/2020/02/12/2020.02.12.945790.short
4100  - http://biorxiv.org/content/early/2020/02/12/2020.02.12.945790.full
AB  - 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 promotes 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) exhibits reduced binding to JMJD3 and impaired cardiomyogenesis. Thus, we have identified an epigenetic mechanism wherein canonical TGF-β pathway activation impairs cardiac gene programming by interfering with GATA4-JMJD3 interactions.