Significant progress in cooperative research on obesity regulation mechanisms of the Institute of Genomics

Recently, Yang Yungui, a researcher of the "Hundred People Project" at the Beijing Institute of Genomics, Chinese Academy of Sciences, and Professor He Chuan from the University of Chicago in the United States have discovered that the main target substrate of the fat-related gene FTO (Fat mass and obesity-associated protein) is 6-methyl gland in RNA. Purine (m6A). The article N6-Methyladenosine in Nuclear RNA is the Main Substrate of the Obesity-Associated FTO Protein was published online in the journal Nature Chemical Biology on October 16. This study provides important clues to reveal the mechanism of FTO regulating obesity. Zhao Xu, PhD student of the Yang Yungui research group of the Institute of Genomics, participated in the research of this project and is the co-first author of this paper.

The main substrate of the obesity-related gene FTO is 6 methyladenine in RNA

At present, obesity has become one of the five major epidemic diseases in the world, seriously endangering the health of the population. About 1.6 billion adults worldwide are overweight and 400 million are obese. The overweight and obesity rates of adults in China are 32.1% and 9.9%, respectively. Obesity is one of the main causes of type 2 diabetes and cardiovascular disease, and is closely related to the occurrence of osteoarthritis and certain cancers. The key to treating obesity is to find genes related to obesity. A genome-wide association study has found that more than 600 gene loci are associated with obesity. Among them, FTO is defined as the first obesity gene because it has been closely related to obesity in a large number of different populations. Through sequence alignment, the researchers found that FTO has a functional domain of E. coli AlkB plus the demethylase activity of the dioxygenase family. Both FTO gene knockout and overexpression mouse models exhibited changes in body weight and adipose tissue abnormalities. But since the discovery of FTO, its mechanism of action has not been reported.

6 methyladenine (m6A) is the main methylation form present in mRNA. On average, each mRNA contains 3-5, which is present in the conserved sequence RGACU (R = G, A, U). There are differences in m6A levels of different gene mRNAs. m6A may be related to mRNA shearing, transportation and other processing processes. But the biological function of m6A in mRNA is unclear. Studies in Arabidopsis found that m6A methylase MTA and its interacting protein AtFIP37 are all located in the mRNA splicing factor "warehouse" speckle. It is speculated that the change of m6A level may affect the variable splicing form of related genes, thereby causing special phenotypic characteristics.

In this study, in vitro simulation of the demethylation reaction conditions under physiological conditions, FTO wild-type and mutant proteins were incubated with methylated substrates, using mass spectrometry and high-performance liquid phase technology, to a variety of methylation forms Through exploration, it was finally found that FTO has a demethylation function for m6A on single-stranded RNA. At the same time, in vivo experiments confirmed that m6A levels in mRNA increased in FTO gene knockdown cells; on the contrary, m6A levels in mRNA decreased in FTO overexpressing cells; while the expression of m6A methylase METTL3 was not affected. Immunofluorescence experiments confirmed that FTO showed a punctate distribution in the nucleus. Through co-staining with various subcellular organelle marker molecules in the nucleus, FTO was found to be partially co-localized with speckle marker molecules SC35, U4 / U6.U5 snRNA-related protein SART1, transcriptase RNA PolII (Ser phosphorylation at position 2). After transcriptional repression, similar to RNA PolII (Ser phosphorylation at position 2), FTO will accumulate in speckle. The m6A methylase METTL3 is also located in speckle. Therefore, FTO may participate in mRNA processing by regulating the reversal of m6A methylation on mRNA.

After the completion of this research work, the genes corresponding to FTO and its m6A methylated mRNA substrate may become candidate targets for the diagnosis and treatment of obesity, and the discovery of the demethylation function of m6A by the obesity-related gene FTO significance. The publication of this paper undoubtedly provides important evidence for RNA methylation modification as a new concept of generalized epigenetics with important biological regulatory functions.

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