TGF-β/Smad信号通路通过控制组蛋白H4K20甲基化修饰调控细胞复制性衰老研究

Epigenetic programming plays a very important role in replicative senescence. Epigenetic modifications are capable of control gene expression, DNA replication and cell aging. Preliminary study found that TGF-β/Smad signaling pathway regulates replicative senescence through controlling H4K20 methylation. TGF-β/Smad possibly control expression of microRNA, which targets mRNA of H4K20 methyltransferase， leads to the decreased level of H4K20 methylation, genome instability and inhibition of DNA repair, finally promotes cell aging. Further research will attempt to explore the regulation mechanism of H4K20 methyltransferase expression by TGF-β/Smad signaling pathway, to analyze the function of H4K20 methylation on replicative senescence, to understand the role of TGF-β/Smad/H4K20 methylation pathway on programmed cell aging during development.

表观遗传修饰在调控细胞复制性衰老中起着重要的作用。表观遗传修饰可以调控基因的表达、DNA复制以及基因组的稳定性。初步研究发现TGF-β/Smad信号通路能够控制H4K20甲基化水平来调控细胞复制性衰老。TGF-β/Smad信号通路可能通过microRNA的表达来调控H4K20甲基化酶的表达，进而造成H4K4甲基化水平的下降、基因组的不稳定和DNA复制的抑制，最终促进衰老。本课题将深入研究TGF-β/Smad信号通路调控H4K20甲基化酶基因表达机理，分析H4K20甲基化与细胞衰老的相互作用关系，研究这条通路在个体发育中对于程序化衰老的调控作用。

本课题针对衰老信号分子TGF-β诱导衰老的机制进行研究。揭示了TGF-β/Smad信号通路被环境压力激活后能够通过导致表观遗传修饰状态的改变，调控细胞衰老和心脏老化的分子机制；阐述了在细胞衰老过程中，由衰老活跃增强子介导的的染色质空间变化来促进下游SASP基因表达的新型作用机制；在国际知名杂志上发表文章两篇，申请到专利一项。