Volume 24, No 12, Dec 2014
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 24 Issue 12, December 2014: 1403-1419 | Open Access
ORIGINAL ARTICLES
FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis
Xu Zhao1,2,*, Ying Yang1,2,*, Bao-Fa Sun1,*, Yue Shi1,2,*, Xin Yang1,2, Wen Xiao1,2, Ya-Juan Hao1,2, Xiao-Li Ping1,2, Yu-Sheng Chen1,2, Wen-Jia Wang1,2, Kang-Xuan Jin1,2, Xing Wang1,2, Chun-Min Huang1, Yu Fu3, Xiao-Meng Ge1, Shu-Hui Song1, Hyun Seok Jeong4, Hiroyuki Yanagisawa5, Yamei Niu6, Gui-Fang Jia7, Wei Wu3, Wei-Min Tong6, Akimitsu Okamoto4,5, Chuan He7,8, Jannie M Rendtlew Danielsen1,9, Xiu-Jie Wang10 and Yun-Gui Yang1
1Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Acaemy of Sciences, No. 1-7 Beichen West Road, Chaoyang District, Beijing 100101, China
2University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China
3Protein Science Laboratory of the Ministry of Education, School of Life Sciences, Tsinghua University, Qinghuayuan 1, Beijing 100084, China
4Research Center for Advanced Science and Technology, the University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
5RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
6Department of Pathology, Center for Experimental Animal Research, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
7Department of Chemical Biology, Beijing National Laboratory for Molecular Sciences, Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
8Department of Chemistry, Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA
9The Novo Nordisk Foundation Center for Protein Research, Ubiquitin Signalling Group, Faculty of Health Sciences, Blegdamsvej 3b, 2200 Copenhagen, Denmark
10Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Correspondence: Yun-Gui Yang, Tel/Fax: +86-10-84097642 (ygyang@big.ac.cn)
The role of Fat Mass and Obesity-associated protein (FTO) and its substrate N6-methyladenosine (m6A) in mRNA processing and adipogenesis remains largely unknown. We show that FTO expression and m6A levels are inversely correlated during adipogenesis. FTO depletion blocks differentiation and only catalytically active FTO restores adipogenesis. Transcriptome analyses in combination with m6A-seq revealed that gene expression and mRNA splicing of grouped genes are regulated by FTO. M6A is enriched in exonic regions flanking 5′- and 3′-splice sites, spatially overlapping with mRNA splicing regulatory serine/arginine-rich (SR) protein exonic splicing enhancer binding regions. Enhanced levels of m6A in response to FTO depletion promotes the RNA binding ability of SRSF2 protein, leading to increased inclusion of target exons. FTO controls exonic splicing of adipogenic regulatory factor RUNX1T1 by regulating m6A levels around splice sites and thereby modulates differentiation. These findings provide compelling evidence that FTO-dependent m6A demethylation functions as a novel regulatory mechanism of RNA processing and plays a critical role in the regulation of adipogenesis.
10.1038/cr.2014.151N6-methyladenosine (m6A); METTL3; FTO; mRNA splicing; adipogenesis
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