miR-122激活肝脏特异性基因在肝细胞特性维持和肝癌发生中的作用

MicroRNAs (miRNAs) are a class of endogenous non-coding RNAs with regulatory functions. Traditionally, miRNAs are thought to play a negative regulatory role in the cytoplasm by binding to the 3'UTR of target genes to degrade mRNA or inhibit translation. However, it remains a challenge to interpret the potential function of many miRNAs located in the nucleus. In our previous study, we found that miRNA in the nucleus activates gene expression at the whole genome level through the enhancers. Recently, we reported a new type of miRNAs present in the nucleus, which can activate gene expression by binding to the enhancers, and named them Nuclear Activating miRNAs (NamiRNAs). MiR-122 is known to display a pattern of tissue-specific and is highly expressed in liver tissue, while it is down-regulated in hepatoma. Emerging evidence shows that miR-122 is closely related to the hepatic cell identity decision and function maintenance. Loss of miR-122 led to liver dysfunction in mice and even induced liver cancer. How to maintain the cell characteristics for hepatic cells and how to participate in the hepatocarcinogenesis for miR-122 are not fully clear. Here, we try to utilize our NamiRNA－enhancer－target gene activation network model to demonstrate the new role of miR-122 on activating the liver specific genes in liver cell identity maintenance and hepatoma development. We believe this project not only helps to better understand the roles of tissue-specific miRNA and enhancer in cell identity decision, but also expands the theory of nuclear miRNA activation and boosts its wide application.

miRNA被认为在细胞浆中通过结合3’UTR抑制翻译或降解靶基因而发挥负向调控作用，但越来越多证据显示miRNA也定位于细胞核。我们前期研究发现细胞核内miRNA通过增强子在全基因组水平激活基因表达。肝特异性miR-122定位于肝细胞核，有证据显示miR-122与肝细胞特性和功能密切相关，miR-122缺失导致小鼠肝功能异常并诱发肝癌，但miR-122如何维持正常肝细胞特征与如何参与肝癌发生确切机制并不清楚。本项目基于我们提出的核内miRNA—增强子—靶基因激活理论，研究肝脏特异的miR-122对肝细胞特性维持及激活增强子的具体分子机制，探讨miR-122缺失与肝细胞特性维持失调以及肝癌发生发展的内在联系，力求阐明miR-122在肝细胞特性维持和肝癌发生发展中的关键作用。本项目不仅有助于理解组织特异性miRNA和增强子在细胞身份识别中的作用，同时拓展核内miRNA激活理论并促进其广泛应用。

肝脏是一个重要的葡萄糖代谢器官，由过多的热量摄入或肥胖引起的肝脏代谢疾病是T2D发展的一个风险因素。目前我们对T2D的发病机制和治疗策略还缺乏了解，但可以确定microRNAs在包括T2D在内的代谢性疾病中起着十分重要的作用。miR-122是一个肝脏特异性microRNA,可定位于肝细胞核，有证据显示miR-122与肝细胞特性和功能密切相关，miR-122缺失导致小鼠肝功能异常，但miR-122如何维持正常肝细胞特征与如何参与肝脏葡萄糖稳态确切机制并不清楚。.本项目中，我们观察到miR-122在T2D患者和高脂饮食小鼠中的表达明显降低。敲除miR-122可以抑制Huh7、A673、293T和3T3L1细胞的葡萄糖消耗并诱发胰岛素抵抗。此外，通过agomiR过量表达miR-122可以增强葡萄糖的消耗，缓解高脂饮食小鼠的胰岛素抵抗。从机制上讲，miR-122作为一种NamiRNA，可以激活葡萄糖摄取和代谢相关的基因，如HNFs、FOXA1和GLUTs，通过miRNA—增强子— 靶基因激活网络维持肝细胞特性及功能。总之，我们目前的研究为T2D的发生提供了一种新的分子机制，并为miR-122 agomiR治疗T2D提供了潜在的治疗策略。.目前，本项目已经取得了丰富的研究成果，已发表9篇SCI论著，且在本项目执行期间成功培养了6名博士研究生，圆满完成了本项目的相关要求。