Divergent Requirements for EZH1 in Heart Development Versus Regeneration

Shanshan Ai; Xianhong Yu; Yumei Li; Yong Peng; Chen Li; Yanzhu Yue; Ge Tao; Chuanyun Li; William T Pu; Aibin He

doi:10.1161/CIRCRESAHA.117.311212

Divergent Requirements for EZH1 in Heart Development Versus Regeneration

Circ Res. 2017 Jul 7;121(2):106-112. doi: 10.1161/CIRCRESAHA.117.311212. Epub 2017 May 16.

Authors

Shanshan Ai¹, Xianhong Yu¹, Yumei Li¹, Yong Peng¹, Chen Li¹, Yanzhu Yue¹, Ge Tao¹, Chuanyun Li¹, William T Pu¹, Aibin He²

Affiliations

¹ From the Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, China (S.A., Y.L., C.L., Y.Y., C.L., A.H.); Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, China (X.Y., Y.P., A.H.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX (G.T.); Department of Cardiology, Boston Children's Hospital, MA (W.T.P.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (W.T.P.).
² From the Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, China (S.A., Y.L., C.L., Y.Y., C.L., A.H.); Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, China (X.Y., Y.P., A.H.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX (G.T.); Department of Cardiology, Boston Children's Hospital, MA (W.T.P.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (W.T.P.). ahe@pku.edu.cn.

Abstract

Rationale: 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.

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^-/- (Ezh1 knockout) and Ezh2^f/f::cTNT^-Cre (Ezh2 knockout) embryos. Ablation of both genes in Ezh1^-/-::Ezh2^f/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 EZH2 likewise improved heart function and stimulated cardiac myocyte 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.

Keywords: lysine; methylation; myocardium; polycomb repressive complex 2; regeneration.

Publication types

Comparative Study

MeSH terms

Animals
Animals, Newborn
Embryonic Development / physiology*
Heart / embryology*
Heart / growth & development
Heart / physiology*
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Myocytes, Cardiac / metabolism
Polycomb Repressive Complex 2 / biosynthesis*
Polycomb Repressive Complex 2 / deficiency
Regeneration / physiology*

Substances

Ezh1 protein, mouse
Polycomb Repressive Complex 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding