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FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis
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FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis
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FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis
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Journal Article
FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis
2014
Overview
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 adi- pogenesis. 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 over- lapping 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 adipogenie 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Adenosine - analogs & derivatives
/ Alpha-Ketoglutarate-Dependent Dioxygenase FTO
/ Animals
/ Biomedical and Life Sciences
/ Core Binding Factor Alpha 2 Subunit - genetics
/ Core Binding Factor Alpha 2 Subunit - metabolism
/ FTO
/ Mice
/ Mixed Function Oxygenases - metabolism
/ Obesity
/ Original
/ Oxo-Acid-Lyases - metabolism
/ RNA剪接
/ 剪接位点
/ 去甲基化
/ 基因表达
/ 相关蛋白
/ 脂肪形成
/ 调控因子
