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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.

SUBMITTER: Zhao X

PROVIDER: S-EPMC4260349 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Zhao Xu X Yang Ying Y Sun Bao-Fa BF Shi Yue Y Yang Xin X Xiao Wen W Hao Ya-Juan YJ Ping Xiao-Li XL Chen Yu-Sheng YS Wang Wen-Jia WJ Jin Kang-Xuan KX Wang Xing X Huang Chun-Min CM Fu Yu Y Ge Xiao-Meng XM Song Shu-Hui SH Jeong Hyun Seok HS Yanagisawa Hiroyuki H Niu Yamei Y Jia Gui-Fang GF Wu Wei W Tong Wei-Min WM Okamoto Akimitsu A He Chuan C Rendtlew Danielsen Jannie M JM Wang Xiu-Jie XJ Yang Yun-Gui YG

Cell research 20141121 12

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 i ...[more]

PMID: 25412662

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Project description:BackgroundN6-methyladenosine (m6A) modification is the most common chemical modification in mammalian mRNAs, and it plays important roles by regulating several cellular processes. Previous studies report that m6A is implicated in modulating tumorigenesis and progression. However, dysregulation of m6A modification and effect of m6A demethylase fat-mass and obesity-associated protein (FTO) on glucose metabolism has not been fully elucidated in papillary thyroid cancer (PTC).MethodsQuantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry were performed to explore the expression profile of FTO in PTC tissues and adjacent non-cancerous thyroid tissues. Effects of FTO on PTC glycolysis and growth were investigated through in vitro and in vivo experiments. Mechanism of FTO-mediated m6A modification was explored through transcriptome-sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-qPCR, luciferase reporter assays, RNA stability assay and RNA immunoprecipitation assay.ResultsFTO expression was significantly downregulated in PTC tissues. Functional analysis showed that FTO inhibited PTC glycolysis and growth. Further analyses were conducted to explore FTO-mediated m6A modification profile in PTC cells and Apolipoprotein E (APOE) was identified as the target gene for FTO-mediated m6A modification using RNA-seq and MeRIP-seq. FTO knockdown significantly increased APOE mRNA m6A modification and upregulated its expression. FTO-mediated m6A modification of APOE mRNA was recognized and stabilized by the m6A reader IGF2BP2. The findings showed that APOE also promoted tumor growth through glycolysis in PTC. Analysis showed that FTO/APOE axis inhibits PTC glycolysis by modulating IL-6/JAK2/STAT3 signaling pathway.ConclusionFTO acts as a tumor suppressor to inhibit tumor glycolysis in PTC. The findings of the current study showed that FTO inhibited expression of APOE through IGF2BP2-mediated m6A modification and may inhibit glycolytic metabolism in PTC by modulating IL-6/JAK2/STAT3 signaling pathway, thus abrogating tumor growth.

Dataset Information

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

Publications

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

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