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.

Zfp281 orchestrates interconversion of pluripotent states by engaging Ehmt1 and Zic2

“…This is reminiscent of lineage‐specifying TFs that are specifically expressed in the lineages they instruct (Graf & Enver, ). In adult mice, Zfp281 is indeed transcribed strongest in heart tissue and its overexpression in fibroblasts enhances cardiac reprogramming (Zhou et al , ). During ESC differentiation, however, Zfp281 neither changes expression nor occupies distinct genomic sites, indicating a facilitating, rather than specifying, function.…”

Therapeutic approaches for cardiac regeneration and repair

“…Using an unbiased screen of human transcription factors, the zinc-finger protein ZNF281 was identified as an inducer of cardiac reprogramming 123 . Addition of ZNF281 to the reprogramming cocktail suppressed the expression of genes associated with the inflammatory response and modulated cardiac gene expression by interacting with the transcription factor GATA4 (REF 123 ).…”

“…Using an unbiased screen of human transcription factors, the zinc-finger protein ZNF281 was identified as an inducer of cardiac reprogramming 123 . Addition of ZNF281 to the reprogramming cocktail suppressed the expression of genes associated with the inflammatory response and modulated cardiac gene expression by interacting with the transcription factor GATA4 (REF 123 ). In other studies, suppressing the expression of genes encoding certain factors such as the Polycomb complex protein BMI1 and the splicing factor polypyrimidine tract-binding protein 1 (PTB) enhanced cardiac reprogramming, suggesting that these factors act as barriers to cardiac repro- gramming 124,125 .…”

Bmi1 inhibitor PTC-209 promotes Chemically-induced Direct Cardiac Reprogramming of cardiac fibroblasts into cardiomyocytes

“…Muraoka et al, indeed, demonstrated that diclofenac sodium treatment greatly enhanced GMT-dependent cardiac reprogramming in postnatal and adult fibroblasts, but not in MEFs, via the inhibition of cyclooxygenase-2 /prostaglandin E2/PGE receptor 4/interleukin 1β/interleukin 1 receptor type 1 signalling and subsequent suppression of inflammatory and fibroblast gene programs 34 . Previous report also identified ZNF281 transcription factor as a robust and efficient activator of adult DCR through its association with Gata4 by inhibiting inflammatory signalling 35 . Moreover, there is growing evidence that innate immunity is a crucial regulator of tissue healing in neonatal hearts 36 .…”