6甲基腺嘌呤（m6A）是mRNA主要修饰形式,但其调控mRNA代谢功能未知。其甲基转移酶复合物METTL3/METTL14/WTAP和去甲基化酶FTO和ALKBH5的发现，首次证实m6A修饰的可逆性，提示m6A调控mRNA代谢。m6A修饰形成维持机制及其调控mRNA代谢，已成为RNA甲基化表观转录组学研究新领域的重要科学问题。在前期研究中，申请人筛选到35个与m6A甲基转移酶三聚体互作候选蛋白，发现METTL3与多种组蛋白修饰共定位及非编码microRNA调控m6A修饰水平，提示这类表观因子调控m6A甲基转移酶。本项目整合多组学(表观修饰、蛋白组、基因组)等交叉学科技术，鉴定m6A甲基转移酶全酶组分及其表观调控因子组蛋白修饰和microRNA，解析m6A与mRNA代谢和疾病关联，阐明m6A修饰形成维持机制，为m6A修饰作为mRNA新顺式调控元件和揭示RNA表观转录组学核心规律提供理论依据。

In messenger RNA (mRNA) methylation is mainly found on N6-adenosine generating N6-methyl-adenosine (m6A), but how it regulates mRNA metabolism remains largely unknown. The applicant identified for the first time the m6A methyltransferase tricomplex METTL3/METTL14/WTAP catalyzing the m6A formation and the only two known m6A demethylases FTO and ALKBH5 that via an oxidative reaction removes the methylgroup on m6A. The dynamic regulation of m6A methylation is important for energy metabolism and spermatogenesis. The discovery of the RNA m6A methyltransferases and the demethylases demonstrate that besides the vital role of DNA and histone methylation, m6A methylation on RNA also plays essential roles in epigenetic regulation of basic life processes in mammals and is now considered a novel epitranscriptomic marker of profound biological significance. The regulation of m6A formation and maintenance and its regulatory roles in mRNA metabolism has therefore now become a new frontier in RNA biology research. .In our new preliminary studies, we screened 35 potential candidates interacting with the m6A methyltransferase tricomplex, and found that METTL3 co-localizes with several histone modifications and that non-coding microRNA regulates cellular mRNA m6A modification levels. These results suggest that epi-regulatory factors such as histone modifications and microRNA may regulate the m6A methyltransferase and modulate m6A level. By integrating multi-cross-disciplinary omics technologies including epi-modifications, proteomics, genomics, etc., this project aims at identifying new enzymatic components of the m6A methyltransferase complex as well as epi-regulatory factors including histone modifications and microRNA and determine their function in mRNA metabolism and potential association with human diseases. Unveiling of the molecular mechanisms of m6A formation and maintenance will provide compelling evidences directly supporting the m6A-modified RRACH (R=G,A; H=A,C,U) sequences in mRNA as new cis-regulatory elements, and provide new important insights into the mechanistics of RNA transcriptomics..