College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Nutrition & Feed Sciences, Ministry of Agriculture, Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Nutrition & Feed Sciences, Ministry of Agriculture, Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
Biochim Biophys Acta Gene Regul Mech. 2019 Aug;1862(8):796-806. doi: 10.1016/j.bbagrm.2019.06.008. Epub 2019 Jul 8.
N-methyladenosine (mA), the most abundant internal mRNA modification in eukaryotes, plays a vital role in regulating adipogenesis. However, its underlying mechanism remains largely unknown. Here, we reveal that deletion of mA demethylase FTO in porcine and mouse preadipocytes inhibits adipogenesis through JAK2-STAT3-C/EBPβ signaling. Mechanistically, FTO deficiency suppresses JAK2 expression and STAT3 phosphorylation, leading to attenuated transcription of C/EBPβ, which is essential for the early stage of adipocyte differentiation. Using dual-luciferase assay, we validate that knockdown of FTO reduces expression of JAK2 in an mA-dependent manner. Furthermore, we find that mA "reader" protein YTHDF2 directly targets mA-modified transcripts of JAK2 and accelerates mRNA decay, which results in decreased JAK2 expression and inactivated JAK2-STAT3-C/EBPβ signaling, thereby inhibiting adipogenesis. Collectively, our results provide a novel insight into the molecular mechanism of mA methylation in post-transcriptional regulation of JAK2-STAT3-C/EBPβ signaling axis and highlight the crucial role of mA modification and its modulators in adipogenesis.
N6-甲基腺苷（m6A）是真核生物中最丰富的内部 mRNA 修饰物，在调节脂肪生成中发挥着重要作用。然而，其潜在机制在很大程度上尚不清楚。在这里，我们揭示了脂肪量与肥胖相关基因（FTO）在猪和小鼠前体脂肪细胞中的缺失通过 JAK2-STAT3-C/EBPβ 信号通路抑制脂肪生成。在机制上，FTO 缺乏会抑制 JAK2 的表达和 STAT3 的磷酸化，从而减弱 C/EBPβ 的转录，这对于脂肪细胞分化的早期阶段至关重要。通过双荧光素酶报告基因检测实验，我们验证了 FTO 的缺失以 m6A 依赖性方式降低了 JAK2 的表达。此外，我们发现 m6A“阅读器”蛋白 YTHDF2 直接靶向 JAK2 的 m6A 修饰转录本，并加速 mRNA 降解，导致 JAK2 表达减少和 JAK2-STAT3-C/EBPβ 信号通路失活，从而抑制脂肪生成。总之，我们的研究结果为 m6A 甲基化在 JAK2-STAT3-C/EBPβ 信号轴的转录后调控中的分子机制提供了新的见解，并强调了 mA 修饰及其调节剂在脂肪生成中的关键作用。
