Divergent Requirements for EZH1 in Heart Development Versus Regeneration
Rationale: Polycomb repressive complex 2 (PRC2) 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 two alternative catalytic subunits with partial functional redundancy. The relative roles of EZH1 and EZH2 in heart development and regeneration are unknown.
Objective: We compared the roles of EZH1 versus EZH2 in heart development and neonatal heart regeneration.
Methods and Results: Heart development was normal in Ezh1-/- (E1KO) and Ezh2f/f::cTNT-Cre (E2KO) embryos. Ablation of both genes in Ezh1-/ ::Ezh2f/f::cTNT-Cre(DKO) embryos caused lethal heart malformations, including hypertrabeculation, compact myocardial hypoplasia, and ventricular septal defect. Epigenome and transcriptome profiling showed that de-repressed genes were upregulated in a manner consistent with total "EZH" dose. In neonatal heart regeneration, Ezh1 was required but Ezh2 was dispensible. This finding was further supported by rescue experiments: cardiac myocyte-restricted re-expression of EZH1 but not EZH2 restored neonatal heart regeneration in E1KO. In MI performed outside of the neonatal regenerative window, EZH1 but not EZH2 likewise improved heart function and stimulated CM proliferation. Mechanistically, EZH1 occupied and activated genes related to cardiac growth.
Conclusions: Our work unravels divergent mechanisms of EZH1 in heart development and regeneration, which will empower efforts to overcome epigenetic barriers to heart regeneration.
- Received April 27, 2017.
- Revision received May 12, 2017.
- Accepted May 15, 2017.