FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis.
FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis.
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N6-甲基腺苷的 FTO 依赖性去甲基化调节 mRNA 剪接，是脂肪生成所必需的
作者：
脂肪量与肥胖相关蛋白（FTO）及其底物N6 - 甲基腺苷（m6A）在mRNA加工和脂肪生成中的作用在很大程度上仍不明确。我们发现，在脂肪生成过程中，FTO的表达与m6A水平呈负相关。FTO缺失会阻断脂肪细胞分化，只有具有催化活性的FTO才能恢复脂肪生成。转录组分析结合m6A测序显示，FTO可调控成组基因的基因表达和mRNA剪接。m6A在5′ - 和3′ - 剪接位点两侧的外显子区域富集，在空间上与mRNA剪接调控的富含丝氨酸/精氨酸（SR）蛋白外显子剪接增强子结合区域重叠。FTO缺失导致m6A水平升高，这会增强SRSF2蛋白与RNA的结合能力，从而增加靶向外显子的包含。FTO通过调节剪接位点周围的m6A水平来控制脂肪生成调节因子RUNX1T1的外显子剪接，进而调控脂肪细胞分化。这些发现提供了有力证据，表明FTO依赖的m6A去甲基化作为一种新的RNA加工调控机制，在脂肪生成的调控中发挥着关键作用。
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.
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影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
Krainer, AR
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
5.2
作者：
Berulava, Tea;Ziehe, Matthias;Horsthemke, Bernhard
通讯作者：
Horsthemke, Bernhard
通过小鼠和人 FTO 对单链 DNA 和 RNA 中的 3-甲基胸腺嘧啶和 3-甲基尿嘧啶进行氧化去甲基化。
影响因子：
3.5
作者：
Jia, Guifang;Yang, Cai-Guang;Yang, Shangdong;Jian, Xing;Yi, Chengqi;Zhou, Zhiqiang;He, Chuan
通讯作者：
He, Chuan
影响因子：
64.5
作者：
Braunschweig U;Gueroussov S;Plocik AM;Graveley BR;Blencowe BJ
通讯作者：
Blencowe BJ