FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis
| Autor: | Xin Yang, Wei Wu, Wen Xiao, Xiu-Jie Wang, Chuan He, Wenjia Wang, Yu-Sheng Chen, Kang-Xuan Jin, Shuhui Song, Bao-Fa Sun, Xing Wang, Yamei Niu, Yun-Gui Yang, Xiao-Li Ping, Hyun Seok Jeong, Xu Zhao, Ying Yang, Guifang Jia, Akimitsu Okamoto, Ya-Juan Hao, Xiaomeng Ge, Yue Shi, Jannie M. Rendtlew Danielsen, Wei-Min Tong, Yu Fu, Hiroyuki Yanagisawa, Chun-Min Huang |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Adenosine
endocrine system diseases RNA Splicing Exonic splicing enhancer Biology mRNA splicing Mixed Function Oxygenases chemistry.chemical_compound Exon N6-methyladenosine (m6A) Adipocytes Animals RNA Messenger Molecular Biology Adipogenesis MRNA modification nutritional and metabolic diseases Oxo-Acid-Lyases Cell Biology Molecular biology chemistry Alpha-Ketoglutarate-Dependent Dioxygenase FTO RNA splicing METTL3 Original Article MRNA methylation N6-Methyladenosine FTO |
| Zdroj: | Cell Research |
| ISSN: | 1748-7838 1001-0602 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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