1. Academic Validation
  2. m6A methylation modulates adipogenesis through JAK2-STAT3-C/EBPβ signaling

m6A methylation modulates adipogenesis through JAK2-STAT3-C/EBPβ signaling

  • Biochim Biophys Acta Gene Regul Mech. 2019 Aug;1862(8):796-806. doi: 10.1016/j.bbagrm.2019.06.008.
Ruifan Wu 1 Guanqun Guo 1 Zhen Bi 1 Youhua Liu 1 Yuanling Zhao 1 Nana Chen 1 Fengqin Wang 1 Yizhen Wang 1 Xinxia Wang 2
Affiliations

Affiliations

  • 1 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.
  • 2 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. Electronic address: xinxiawang@zju.edu.cn.
Abstract

N6-methyladenosine (m6A), 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 m6A 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 m6A-dependent manner. Furthermore, we find that m6A "reader" protein YTHDF2 directly targets m6A-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 m6A methylation in post-transcriptional regulation of JAK2-STAT3-C/EBPβ signaling axis and highlight the crucial role of m6A modification and its modulators in adipogenesis.

Keywords

Adipogenesis; FTO; JAK2; STAT3; YTHDF2; m(6)A.

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