心脏发育与再生过程中对EZH1的不同需求。
Divergent Requirements for EZH1 in Heart Development Versus Regeneration.
作者信息
Ai Shanshan, Yu Xianhong, Li Yumei, Peng Yong, Li Chen, Yue Yanzhu, Tao Ge, Li Chuanyun, Pu William T, He Aibin
机构信息
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.).
出版信息
Circ Res. 2017 Jul 7;121(2):106-112. doi: 10.1161/CIRCRESAHA.117.311212. Epub 2017 May 16.
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 (1 knockout) and Ezh2::cTNT (2 knockout) embryos. Ablation of both genes in Ezh1::Ezh2::cTNT 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 1 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.
理论依据
多梳抑制复合物2是一种主要的表观遗传抑制因子，可在组蛋白H3赖氨酸27位点（H3K27me）沉积甲基化，并控制包括心肌细胞在内的许多细胞的分化和功能。EZH1和EZH2是两个具有部分功能冗余的催化亚基。EZH1和EZH2在心脏发育和再生中的相对作用尚不清楚。
目的
我们比较了EZH1和EZH2在心脏发育和新生心脏再生中的作用。
方法与结果
Ezh1（1敲除）和Ezh2::cTNT（2敲除）胚胎的心脏发育正常。Ezh1::Ezh2::cTNT胚胎中两个基因的缺失导致致命的心脏畸形，包括小梁增多、致密心肌发育不全和室间隔缺损。表观基因组和转录组分析表明，去抑制的基因以与总EZH剂量一致的方式上调。在新生心脏再生中，需要Ezh1，但Ezh2是可有可无的。这一发现得到了挽救实验的进一步支持：心肌细胞特异性重新表达EZH1而非EZH2可恢复1敲除小鼠的新生心脏再生。在新生再生窗口之外进行的心肌梗死中，EZH1而非EZH2同样改善了心脏功能并刺激了心肌细胞增殖。从机制上讲，EZH1占据并激活了与心脏生长相关的基因。
结论
我们的工作揭示了EZH1在心脏发育和再生中的不同机制，这将有助于努力克服心脏再生的表观遗传障碍。
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