Divergent Requirements for EZH1 in Heart Development Versus Regeneration.
Divergent Requirements for EZH1 in Heart Development Versus Regeneration.
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EZH1 在心脏发育与再生中的不同要求。
DOI：
10.1161/circresaha.117.311212
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发表时间：
2017-07-07
影响因子：
20.1
通讯作者：
He A
中科院分区：
文献类型：
--
作者：
Ai S;Yu X;Li Y;Peng Y;Li C;Yue Y;Tao G;Li C;Pu WT;He A
基本原理：Polycomb抑制复合物2是一种主要的表观遗传抑制因子，它将组蛋白H3的甲基化沉积在赖氨酸27（H3 K27 me）上，并控制许多细胞（包括心肌细胞）的分化和功能。EZH 1和EZH 2是2个具有部分功能冗余的交替催化亚基。EZH 1和EZH 2在心脏发育和再生中的相对作用尚不清楚。目的：比较EZH 1和EZH 2在心脏发育和新生心脏再生中的作用。方法和结果：Ezh 1 −/−（Ezh 1敲除）和Ezh 2f/f：：cTNT−Cre（Ezh 2敲除）胚胎的心脏发育正常。在Ezh 1 −/−：：Ezh 2f/f：：cTNT−Cre胚胎中切除这两种基因会导致致命的心脏畸形，包括小梁形成过度、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，去阻遏基因上调的方式与总EZH剂量一致。在新生心脏再生过程中，Ezh 1是必需的，但Ezh 2是必需的。这一发现得到了拯救实验的进一步支持：心肌细胞限制性的EZH 1而不是EZH 2的再表达恢复了EZH 1敲除的新生心脏再生。在新生儿再生窗口之外进行的心肌梗死中，EZH 1而不是EZH 2同样改善了心脏功能并刺激了心肌细胞增殖。从机制上讲，EZH 1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EZH 1在心脏发育和再生中的不同机制，这将有助于克服心脏再生的表观遗传障碍。
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 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 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.