TY - JOUR
T1 - Suppression of canonical TGF-β signaling enables GATA4 to interact with H3K27me3 demethylase JMJD3 to promote cardiomyogenesis
AU - Riching, Andrew S.
AU - Danis, Etienne
AU - Zhao, Yuanbiao
AU - Cao, Yingqiong
AU - Chi, Congwu
AU - Bagchi, Rushita A.
AU - Klein, Brianna J.
AU - Xu, Hongyan
AU - Kutateladze, Tatiana G.
AU - McKinsey, Timothy A.
AU - Buttrick, Peter M.
AU - Song, Kunhua
N1 - Funding Information:
The authors thank the University of Colorado School of Medicine Biological Mass Spectrometry Core Facility and the Genomics and Microarray Core Facility. A.S.R. was supported by predoctoral fellowships from the University of Colorado Consortium for Fibrosis Research & Translation, Colorado Clinical & Translational Sciences Institute (TL1 TR001081), and the American Heart Association (18PRE34030030). R.A.B. received a postdoctoral fellowship award from the Canadian Institutes of Health Research (FRN-216927). T.A.M. received funding from National Institute of Health by grants HL116848, HL147558, DK119594, HL127240, HL150225, and a grant from the American Heart Association (16SFRN31400013). K.S. was supported by funds from the Boettcher Foundation, American Heart Association (13SDG17400031), University of Colorado Department of Medicine Outstanding Early Career Scholar Program, Gates Frontiers Fund, and National Institute of Health HL133230. We thank Dr. Aaron Johnson and Dr. David Port for insightful discussion and Dr. Jennifer Major for critical reading and editing of the manuscript. Fig. 7 and the graphical abstract were created using Biorender.com.
Funding Information:
The authors thank the University of Colorado School of Medicine Biological Mass Spectrometry Core Facility and the Genomics and Microarray Core Facility. A.S.R. was supported by predoctoral fellowships from the University of Colorado Consortium for Fibrosis Research & Translation, Colorado Clinical & Translational Sciences Institute ( TL1 TR001081 ), and the American Heart Association ( 18PRE34030030 ). R.A.B. received a postdoctoral fellowship award from the Canadian Institutes of Health Research ( FRN-216927 ). T.A.M. received funding from National Institute of Health by grants HL116848 , HL147558 , DK119594 , HL127240 , HL150225 , and a grant from the American Heart Association ( 16SFRN31400013 ). K.S. was supported by funds from the Boettcher Foundation , American Heart Association ( 13SDG17400031 ), University of Colorado Department of Medicine Outstanding Early Career Scholar Program, Gates Frontiers Fund , and National Institute of Health HL133230 . We thank Dr. Aaron Johnson and Dr. David Port for insightful discussion and Dr. Jennifer Major for critical reading and editing of the manuscript. Fig. 7 and the graphical abstract were created using Biorender.com .
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/4
Y1 - 2021/4
N2 - 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.
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 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.
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U2 - 10.1016/j.yjmcc.2020.12.005
DO - 10.1016/j.yjmcc.2020.12.005
M3 - Article
C2 - 33359755
AN - SCOPUS:85098559195
SN - 0022-2828
VL - 153
SP - 44
EP - 59
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -