心脏是否“只衰不老”一直悬而未决，且目前对调控心脏衰老的机制尚不清楚，评价体系也有待明确。我们前期在自然老化小鼠心脏中发现与细胞衰老相似的表型，如SA-β-gal增加，提示心脏存在衰老过程；同时H3K4组蛋白甲基转移酶menin/MLL复合物表达明显上调，伴心脏发育特异转录因子GATA4、NKX2.5及P16表达增加、端粒酶表达降低；Men1敲除小鼠心脏发育障碍；ChIP-seq发现menin结合在以上基因启动子。我们拟利用已建立的Men1、MLL基因敲除小鼠，探索menin在心脏衰老的生物学功能；筛选鉴定menin调控心脏衰老的关键靶基因，阐明menin调控p16、GATA4、端粒酶等的组蛋白甲基化修饰机制；利用以上模型进一步明确心脏衰老的形态学特征及特异性分子标志物。本研究将探索心脏衰老的规律，从表观遗传学角度深入揭示心脏衰老的关键节点及组蛋白重塑机制。

To date, whether the heart is getting old with the growth of age remains obscure. While, recent researches suggested that cardiomyocytes could devide at a low rate under certain conditions. It reminds us to take a new look at cardiac aging. However, little is known about the mechanism of cardiac aging. Besides, the evaluation system needs to be clear. Previous experimental work showed that senescence-associated β-galactosidase (SA-β-gal) activity increased in hearts of aged rats (22 month), which is consistent with classic senescent phenotype. It suggested that aged heart can obtain key characteristics of senescent cells. In addition, the expression of H3K4 histone methyltransferase menin/MLL complex, cardiac specific transcription factors (e.g. GATA4, NKX2.5 etc) and p16 was significantly increased. While the expression of telomerase expression decreased. Men1 knockout mice showed the dysfunction in heart development. The result of ChIP-seq revealed that menin could bind to the promoter region of above-mentioned genes. Men1 knockout mice will be applied to explore the biological function of menin in cardiac aging, to screen and identify the key target genes of menin and to clarify how the menin regulate p16, GATA4 and telomerase mediated by the mechanism of histone methylation modification. Furthermore, morphological features and specific molecular markers of cardiac aging will be further explicated. Our study will try to define the law of cardiac aging and reveal the key nodes and the mechanism of histone remodeling in cardiac aging from the perspective of epigenetics.