Divergent Requirements for EZH1 in Heart Development Versus Regeneration

Circulation Research
Shanshan AiAibin He

Abstract

Polycomb repressive complex 2 is a major epigenetic repressor that deposits methylation on histone H3 on lysine 27 (H3K27me) and controls differentiation and function of many cells, including cardiac myocytes. EZH1 and EZH2 are 2 alternative catalytic subunits with partial functional redundancy. The relative roles of EZH1 and EZH2 in heart development and regeneration are unknown. We compared the roles of EZH1 versus EZH2 in heart development and neonatal heart regeneration. Heart development was normal in Ezh1-/- (Ezh1 knockout) and Ezh2f/f::cTNT-Cre (Ezh2 knockout) embryos. Ablation of both genes in Ezh1-/-::Ezh2f/f::cTNT-Cre embryos caused lethal heart malformations, including hypertrabeculation, compact myocardial hypoplasia, and ventricular septal defect. Epigenome and transcriptome profiling showed that derepressed genes were upregulated in a manner consistent with total EZH dose. In neonatal heart regeneration, Ezh1 was required, but Ezh2 was dispensable. This finding was further supported by rescue experiments: cardiac myocyte-restricted re-expression of EZH1 but not EZH2 restored neonatal heart regeneration in Ezh1 knockout. In myocardial infarction performed outside of the neonatal regenerative window, EZH1 but not EZ...Continue Reading

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Citations

Aug 30, 2018·Physiological Reviews·Thomas Moore-MorrisMichel Puceat
Jun 9, 2018·Circulation Research·Ruth Williams
May 26, 2018·Circulation Research·Manuel Rosa-GarridoThomas M Vondriska
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