title: FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis.
abstract: 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.
authors.affiliation: 1] Key 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 [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhao
authors.affiliation: 1] Key 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 [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key 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.
authors.forename: Bao-Fa
authors.initials: BF
authors.lastname: Sun
authors.affiliation: 1] Key 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 [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shi
authors.affiliation: 1] Key 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 [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.affiliation: 1] Key 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 [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Xiao
authors.affiliation: 1] Key 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 [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Hao
authors.affiliation: 1] Key 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 [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Ping
authors.affiliation: 1] Key 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 [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chen
authors.affiliation: 1] Key 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 [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Wen-Jia
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: 1] Key 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 [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Kang-Xuan
authors.initials: KX
authors.lastname: Jin
authors.affiliation: 1] Key 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 [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key 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.
authors.forename: Chun-Min
authors.initials: CM
authors.lastname: Huang
authors.affiliation: Protein Science Laboratory of the Ministry of Education, School of Life Sciences, Tsinghua University, Qinghuayuan 1, Beijing 100084, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Key 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.
authors.forename: Xiao-Meng
authors.initials: XM
authors.lastname: Ge
authors.affiliation: Key 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.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Song
authors.affiliation: Research Center for Advanced Science and Technology, the University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Jeong
authors.affiliation: RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yanagisawa
authors.affiliation: Department 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.
authors.forename: Yamei
authors.initials: Y
authors.lastname: Niu
authors.affiliation: Department 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.
authors.forename: Gui-Fang
authors.initials: GF
authors.lastname: Jia
authors.affiliation: Protein Science Laboratory of the Ministry of Education, School of Life Sciences, Tsinghua University, Qinghuayuan 1, Beijing 100084, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department 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.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Tong
authors.affiliation: 1] Research Center for Advanced Science and Technology, the University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan [2] RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: 1] Department 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 [2] Department of Chemistry, Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.affiliation: 1] Key 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 [2] The Novo Nordisk Foundation Center for Protein Research, Ubiquitin Signalling Group, Faculty of Health Sciences, Blegdamsvej 3b, 2200 Copenhagen, Denmark.
authors.forename: Jannie M
authors.initials: JM
authors.lastname: Rendtlew Danielsen
authors.affiliation: Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiu-Jie
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Key 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.
authors.forename: Yun-Gui
authors.initials: YG
authors.lastname: Yang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050156:Adipogenesis; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D007652:Oxo-Acid-Lyases / Q000378:metabolism*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D012333:RNA, Messenger; C493726:Runx1 protein, mouse; C010223:N-methyladenosine; D006899:Mixed Function Oxygenases; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D007652:Oxo-Acid-Lyases; D000241:Adenosine