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Cell Res. 2014 Dec;24(12):1403-19. doi: 10.1038/cr.2014.151. Epub 2014 Nov 21.

FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis.

Author information

1
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.
2
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.
3
Protein Science Laboratory of the Ministry of Education, School of Life Sciences, Tsinghua University, Qinghuayuan 1, Beijing 100084, China.
4
Research Center for Advanced Science and Technology, the University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
5
RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
6
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.
7
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.
8
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.
9
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.
10
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.
11
Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.

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.

PMID:
25412662
PMCID:
PMC4260349
DOI:
10.1038/cr.2014.151
[Indexed for MEDLINE]
Free PMC Article

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