N6-甲基腺嘌呤去甲基酶-肥胖蛋白FTO的分子机理与致病通路研究

Obesity has become a serious worldwide public health concern. The genome-wide association studites (GWAS) made the first connection between obesity and FTO gene. FTO has been shown to affect human obesity and energy homeostasis and has become a prominent target of research in the field. However, the physiological substrate and function of FTO remains unknown, preventing molecular-level understanding of the mechanism and pathway of FTO-mediated regulation, until we found that the major substrate of FTO is N6-methyladenosine（m6A）in nuclear RNA. m6A is a ubiquitous modification in messenger RNA (mRNA) across most eukaryotes. However, the exact functions of m6A have not been clearly understood. The discovery that FTO is an m6A demethylase indicates that this RNA methylation modification is reversible and dynamically regulated, and that analogous to reversible DNA and histone modifications, it may affect gene expression and cell fate decisions by modulating multiple RNA-related cellular pathways, which potentially provides rapid responses to various cellular and environmental signals, including energy and nutrient availability in mammals. We termed it as a new field "RNA Epigenetics".Here we propose to identify the genes targeted directly by FTO and elucidate the mechanism and pathological pathways of FTO at molecular-level by study the function of m6A binding proteins which manipulate FTO targeted m6A and of the FTO partner proteins which control FTO enzyme function.

肥胖已经成为全人类健康和生命的最大威胁。通过全基因组关联性研究首次发现肥胖与FTO基因相关联。研究表明FTO可以调控人体的肥胖和能量动态平衡，已经成为肥胖研究领域主要的研究基因。然而由于一直不知道FTO的生理底物和功能，FTO的分子机理和通路一直都未知，直到我们发现了FTO的主要作用靶标为细胞核RNA上的N6-甲基腺嘌呤(m6A)，为今后的研究方向指明了方向。在真核细胞中m6A是信使RNA（mRNA）上含量最多的修饰碱基，但是具体的功能还未知。m6A去甲基修饰酶的发现，意味着m6A为可逆性动态修饰，有可能会像DNA和组蛋白的修饰一样，可以通过控制多个RNA相关的细胞通路来调控基因表达和决细胞命运。我们将之命名为"RNA表观遗传学"。本项目将鉴定FTO直接作用的目标基因，通过寻找和研究FTO作用的m6A位点的m6A结合蛋白和调控FTO酶活性的FTO协同蛋白的功能来揭示FTO的分子机理和病理。

RNA表观遗传学（表观转录组学）是当前最前沿和热门的科学研究领域之一，Nature在2017年发表专文将其评述为表观遗传学的又一“淘金热”。本课题利用本课题组在RNA表观遗传学领域的领先地位及北京大学的优势，开展广泛的国内外合作。不仅按计划完成了研究目标，还开展了RNA去甲基酶小分子抑制剂及RNA修饰在植物中的研究工作。通过FTO-m6A核酸复合物晶体结构解析了FTO底物选择性；鉴定出FTO相互作用蛋白；发现RNA去甲基化酶FTO的小分子化合物、解析其复合物结 构、阐明其分子机制并开展化学干预研究；首次绘制植物拟南芥全转录组m6A甲基化图谱；发现拟南芥的第一个mRNA m6A去甲基酶。研究成果在Nature Communications、Plant Cell、Nuleic Acids Research等杂志发表致谢本基金号的SCI论文4篇，影响因子>9论文3篇。课题参与研究团队培养博士研究生2名，博士后出站1名，6人次获研究生奖学金和国家奖学金。截止到课题目前为止，已累计到账经费85万，支出经费85万，所有课题经费均按相关规定，按预算执行。