ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression

Huanyu Zhou, Maria Gabriela Morales, Hisayuki Hashimoto, Matthew E. Dickson, Kunhua Song, Wenduo Ye, Min S. Kim, Hanspeter Niederstrasser, Zhaoning Wang, Beibei Chen, Bruce A. Posner, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1770-1783
Number of pages14
JournalGenes and Development
Volume31
Issue number17
DOIs
Publication statusPublished - 2017 Sep 1
Externally publishedYes

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Keywords

  • Anti-inflammation
  • Cardiac gene activation
  • Cardiomyocytes
  • Direct cellular reprogramming
  • Heart regeneration
  • ZFP281

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Zhou, H., Morales, M. G., Hashimoto, H., Dickson, M. E., Song, K., Ye, W., Kim, M. S., Niederstrasser, H., Wang, Z., Chen, B., Posner, B. A., Bassel-Duby, R., & Olson, E. N. (2017). ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression. Genes and Development, 31(17), 1770-1783. https://doi.org/10.1101/gad.305482.117