MINA53通过上调ASPM促进肝再生的作用及机制研究

Liver regeneration plays an important role in the recovery of liver function after surgical resection or liver injury. However, mechanisms underlying liver regeneration remain poorly understood. In the previous study, we found that the expression of histone demethylase MINA53 was significantly increased in 70% hepatectomized mice. Next, hepatectomy was performed in mice with liver-specific deletion of MINA53 gene, which resulted in obviously inhibited liver regeneration and decreased expression of Cyclin E in the residual liver tissue. Previous study has reported that ASPM inhibited the ubiquitination of Cyclin E. Consistently, our results showed that MINA53 could bind to the promoter of ASPM gene and down-regulate its expression in the form of compound with c-Myc and p300, suggesting that MINA53 might regulate Cyclin E through ASPM and promote liver regeneration. In this project, the biological function of MINA53 will be clarified in post-injury condition. Additionally, we will examine the molecular mechanism of MINA53/ASPM/Cyclin E pathway in the process of liver regeneration both in vitro and in vivo.

肝再生对切除术及损伤后肝功能的恢复起到至关重要的作用。前期我们筛选并验证了组蛋白去甲基化酶MINA53在70%肝切除小鼠的肝脏组织中表达显著上升。后续我们对肝脏特异性敲除MINA53基因的小鼠实施肝切除术，发现肝再生过程明显受到抑制，同时小鼠肝组织中Cyclin E表达水平下降。前期研究显示ASPM可抑制Cyclin E的泛素化降解。我们发现MINA53可与转录因子c-Myc及组蛋白乙酰转移酶p300相互作用，以复合物的形式结合于ASPM基因的启动子。此外，敲除MINA53可显著下调ASPM的表达，提示MINA53可能通过ASPM调控Cyclin E，从而促进肝再生过程。在此基础上，本项目拟阐明MINA53在损伤后肝再生过程中的生物学功能；明确MINA53调控ASPM的分子机制；阐明MINA53/ASPM/Cyclin E通路在肝再生过程中的作用机理。

肝再生对切除术及损伤后肝功能的恢复起到至关重要的作用。前期我们筛选并验证了组蛋白去甲基化酶MINA53（MDIG）在70%肝切除小鼠的肝脏组织中表达显著上升。通过本项目的研究，进一步明确了MDIG对肝再生过程的促进作用及其机制，在野生小鼠肝切除术或肝损伤后的再生过程中，MDIG发挥去甲基化酶功能，降低H3K9me3水平，开放染色质，促进Otx2的转录，继而促进Myc的表达，形成MDIG/Otx2/Myc调控轴，通过上调一系列细胞周期蛋白表达，促进细胞周期进展和增殖。敲除肝脏中的MDIG后，小鼠肝再生过程明显受限。该研究证明了MDIG在肝脏再生调控中的关键作用，有助于进一步认识表观调控与肝再生的关系；发现了MDIG在增殖细胞中促进细胞周期进展的重要性，为肝脏疾病的临床治疗提供了必要的理论基础，并支持MDIG作为治疗其他异常增殖疾病(如良性和恶性肿瘤)的一个新的治疗靶点。