腺嘌呤去甲基化酶FTO对2型糖尿病糖脂代谢关键基因的调控作用

项目名称： 腺嘌呤去甲基化酶FTO对2型糖尿病糖脂代谢关键基因的调控作用

项目编号： No.81472023

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘松梅

作者单位： 武汉大学

项目金额： 72万元

中文摘要： N6-甲基腺嘌呤(m6A)是mRNA修饰中最常见类型，在调控基因表达中起重要作用。最新研究表明，与2型糖尿病(T2DM)和肥胖相关的FTO基因编码的蛋白是m6A的特异性去甲基化酶。我们前期发现：①T2DM患者外周血FTO基因高表达，m6A含量明显下降，在糖尿病大鼠血液中存在相同的现象；②m6A含量与空腹血糖、甘油三酯负相关，而与高密度脂蛋白胆固醇正相关；③m6A含量下降是T2DM的风险因子。据此假设：去甲基化酶FTO通过调控m6A修饰而影响糖脂代谢关键基因表达，导致T2DM糖脂代谢紊乱。本课题拟采用最新的m6A修饰的mRNA深度测序(m6A-seq)和液质联用(LC-ESI-MS/MS)技术，从个体、细胞及动物水平明确FTO对糖脂代谢关键基因的调控作用，发现T2DM特异性的差异甲基化基因。本研究将从RNA甲基化新角度探讨糖脂代谢紊乱的发生机制，为T2DM及其并发症的防治提供新思路。

中文关键词： N6-甲基腺嘌呤；腺嘌呤去甲基化酶；2型糖尿病

英文摘要： N6-methyladenosine (m6A) is the most prevalent internal modification in mRNA, which has a fundamental role in regulation of gene expression. Recent studies demonstrated that the fat mass and obesity-associated (FTO) protein, as a risk factor for type 2 diabetes mellitus (T2DM) and obesity, is an m6A-demethylase. Our previous studies have already demonstrated that a significant higher expression level of FTO and lower m6A content were in peripheral blood of T2DM patients and diabetic rats, compared with the normal controls; our results further confirmed that m6A content was not only negatively correlated with fasting blood glucose and triglycerides (TG), but correlated with high-density lipoprotein cholesterol (HDL-C), which implied that decreased m6A content was a risk factor for T2DM. Thus, we hypothesize that FTO regulates m6A dynamic modification and affects the expression levels of the regulatory genes involved in glucose and lipid metabolism, which will lead to impaired functional glucose homeostasis and lipid disorder. To verify the hypothesis, we will analyze T2DM specific expression profiles with contained m6A and confirm FTO plays a key regulation function in those genes involved in glucose and lipid metabolism using m6A-seq and liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis. These results will provide new insights into the pathogenesis of impaired glucose homeostasis and lipid disorder induced by mRNA methylation and novel ideals for the prevention of T2DM and its complications.

英文关键词： N6-methyladenosine;FTO;type 2 diabetes mellitus