ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression

• Published in: Genes & development Vol. 31; no. 17; pp. 1770 - 1783
• Main Authors: Zhou, Huanyu, Morales, Maria Gabriela, Hashimoto, Hisayuki, Dickson, Matthew E, Song, Kunhua, Ye, Wenduo, Kim, Min S, Niederstrasser, Hanspeter, Wang, Zhaoning, Chen, Beibei, Posner, Bruce A, Bassel-Duby, Rhonda, Olson, Eric N
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01-09-2017
• Subjects: Anti-Inflammatory Agents - pharmacology; Cellular Reprogramming - drug effects; Cellular Reprogramming - genetics; Fibroblasts - physiology; GATA4 Transcription Factor - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Genome-Wide Association Study; Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; Research Paper; Transcription Factors - metabolism; Transcriptome; cardiomyocytes; direct cellular reprogramming; anti-inflammation; ZFP281; heart regeneration; cardiac gene activation
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.305482.117

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.