TY - JOUR
T1 - ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression
AU - Zhou, Huanyu
AU - Morales, Maria Gabriela
AU - Hashimoto, Hisayuki
AU - Dickson, Matthew E.
AU - Song, Kunhua
AU - Ye, Wenduo
AU - Kim, Min S.
AU - Niederstrasser, Hanspeter
AU - Wang, Zhaoning
AU - Chen, Beibei
AU - Posner, Bruce A.
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
N1 - Publisher Copyright:
© 2017 Zhou et al.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - Direct reprogramming of fibroblasts to cardiomyocytes represents a potential means of restoring cardiac function following myocardial injury. AKT1 in the presence of four cardiogenic transcription factors, GATA4, HAND2, MEF2C, and TBX5 (AGHMT), efficiently induces the cardiac gene program in mouse embryonic fibroblasts but not adult fibroblasts. To identify additional regulators of adult cardiac reprogramming, we performed an unbiased screen of transcription factors and cytokines for those that might enhance or suppress the cardiogenic activity of AGHMT in adult mouse fibroblasts. Among a collection of inducers and repressors of cardiac reprogramming, we discovered that the zinc finger transcription factor 281 (ZNF281) potently stimulates cardiac reprogramming by genome-wide association with GATA4 on cardiac enhancers. Concomitantly, ZNF281 suppresses expression of genes associated with inflammatory signaling, suggesting the antagonistic convergence of cardiac and inflammatory transcriptional programs. Consistent with an inhibitory influence of inflammatory pathways on cardiac reprogramming, blockade of these pathways with anti-inflammatory drugs or components of the nucleosome remodeling deacetylase (NuRD) complex, which associate with ZNF281, stimulates cardiac gene expression. We conclude that ZNF281 acts at a nexus of cardiac and inflammatory gene programs, which exert opposing influences on fibroblast to cardiac reprogramming.
AB - Direct reprogramming of fibroblasts to cardiomyocytes represents a potential means of restoring cardiac function following myocardial injury. AKT1 in the presence of four cardiogenic transcription factors, GATA4, HAND2, MEF2C, and TBX5 (AGHMT), efficiently induces the cardiac gene program in mouse embryonic fibroblasts but not adult fibroblasts. To identify additional regulators of adult cardiac reprogramming, we performed an unbiased screen of transcription factors and cytokines for those that might enhance or suppress the cardiogenic activity of AGHMT in adult mouse fibroblasts. Among a collection of inducers and repressors of cardiac reprogramming, we discovered that the zinc finger transcription factor 281 (ZNF281) potently stimulates cardiac reprogramming by genome-wide association with GATA4 on cardiac enhancers. Concomitantly, ZNF281 suppresses expression of genes associated with inflammatory signaling, suggesting the antagonistic convergence of cardiac and inflammatory transcriptional programs. Consistent with an inhibitory influence of inflammatory pathways on cardiac reprogramming, blockade of these pathways with anti-inflammatory drugs or components of the nucleosome remodeling deacetylase (NuRD) complex, which associate with ZNF281, stimulates cardiac gene expression. We conclude that ZNF281 acts at a nexus of cardiac and inflammatory gene programs, which exert opposing influences on fibroblast to cardiac reprogramming.
KW - Anti-inflammation
KW - Cardiac gene activation
KW - Cardiomyocytes
KW - Direct cellular reprogramming
KW - Heart regeneration
KW - ZFP281
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U2 - 10.1101/gad.305482.117
DO - 10.1101/gad.305482.117
M3 - Article
C2 - 28982760
AN - SCOPUS:85031005769
SN - 0890-9369
VL - 31
SP - 1770
EP - 1783
JO - Genes and Development
JF - Genes and Development
IS - 17
ER -