ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression.

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.

journal_name

Genes Dev

journal_title

Genes & development

authors

Zhou H,Morales MG,Hashimoto H,Dickson ME,Song K,Ye W,Kim MS,Niederstrasser H,Wang Z,Chen B,Posner BA,Bassel-Duby R,Olson EN

doi

10.1101/gad.305482.117

subject

Has Abstract

pub_date

2017-09-01 00:00:00

pages

1770-1783

issue

17

eissn

0890-9369

issn

1549-5477

pii

31/17/1770

journal_volume

31

pub_type

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