EZH1调控心脏发育与再生的差异机制研究

Whether mammalian heart regeneration is a natural event recapitulating both early heart development and its developmental gene programs remains elusive. Undoubtedly, understanding of heart development and regeneration will complement one another. Here, we study the differential roles of EZH1/2 in heart development and regeneration. Our preliminary results showed that EZH1 and EZH2 displayed redundant roles in orchestrating the early heart development through repressing the non-essential heart gene programs by depositing the repressive histone mark H3K27me3. Surprisingly, Ezh1 but not Ezh2 deletion reduced the potential of spontaneous neonatal heart regeneration of mice, and the in vivo re-expression of EZH1 but not EZH2 was able to remarkably rescue the heart regeneration capacity in Ezh1 mutants. Following up these results, we hypothesize that EZH1 plays the divergent roles depending on the distinct epigenetic landscape in these two processes. Specifically, we set up the three aims: 1. Define epigenetic mechanisms of how EZH1 promotes neonatal heart regeneration; 2. Identify the cellular mechanisms of EZH1 mediated expansion of subpopulation of cardiomyocytes; 3. Explore the therapeutic potential of EZH1 gain of function for adult heart regeneration. Through the completion of these goals, we will uncover the convergent and divergent mechanisms in heart development and regeneration, and provide a precise epigenetic regulatory network on mammalian heart regeneration.

心脏再生是否为心脏发育过程以及其调控网络的重演目前尚不清楚。了解发育的表观遗传调节机制对心脏再生具有理论指导意义。前期未发表结果表明表观调控因子EZH1/2在调节早期心脏发育中，通过抑制心肌细胞非必需基因，发挥表观遗传机制的互补性作用；敲除Ezh1而非Ezh2将抑制新生期心脏再生潜能；转基因过表达Ezh1而非Ezh2能显著恢复Ezh1敲除导致的心肌再生受损表型。本项目提出科学假设：在调控心脏再生与发育过程中，因染色质图谱环境不同，EZH1通过不同分子机制发挥作用，并能促进心肌梗死后的心脏再生潜能。我们设置如下目标：1. 阐明EZH1促进新生期心脏再生的表观遗传机制；2. 阐明EZH1促心肌细胞增殖的细胞学机制；3. 探索EZH1过表达对成体心脏再生的作用。上述目标的完成不仅能揭示心脏发育与再生的调节机制的异同，也能帮助我们绘制更精细的心脏再生关键表观调控机制。

哺乳动物的成体心脏再生能力微弱，但出生1-7天的新生期小鼠具有自发再生能力。重启心脏早期发育过程中的关键基因程序与表观遗传机制是否能促进成体心脏再生尚不清楚。PRC2复合体在心脏发育早期发挥重要调控作用，且其核心催化亚基EZH1/EZH2在心脏发育过程中呈现动态表达模式。然而，EZH1/EZH2是否及如何参与调控心脏发育及再生过程尚不明确。.本项目从发育和再生两个阶段入手，系统探究了PRC2亚基EZH1/EZH2在心脏发育及再生过程中的调控功能，并揭示：在小鼠胚胎心脏发育过程中EZH2是主要的甲基转移酶，同时EZH1能与EZH2功能互补，通过建立H3K27me3修饰抑制非心脏基因表达，表现出“EZH”剂量效应，协调心脏发育。在新生期小鼠心脏再生过程中，EZH1而不是EZH2发挥必要调控功能，EZH1能与组蛋白修饰H3K27me1和H3K4me3相互作用，激活心肌生长相关基因的表达，促进心肌细胞的增殖，提高心脏再生能力。该项目系统证实EZH1以不同的表观调控机制同时控制心脏发育（抑制性）和再生（激活性）两个过程，揭示心脏再生过程并不是简单重启心脏发育的一套表观调控网络。因此为促进成体心脏心肌细胞的增殖，需要正确认识表观遗传因子调控胚胎期心肌细胞增殖的分子机制。该项目将为心脏再生医学研究提供新的理论指导。