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METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPβ pathway via an m 6 A‐YTHDF2–dependent manner
Author(s) -
Yao Yongxi,
Bi Zhen,
Wu Ruifan,
Zhao Yuanling,
Liu Youhua,
Liu Qing,
Wang Yizhen,
Wang Xinxia
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201802644r
Subject(s) - adipogenesis , stat5 , gene knockdown , microbiology and biotechnology , stat protein , mesenchymal stem cell , stat3 , ccaat enhancer binding proteins , chemistry , stem cell , cellular differentiation , biology , transcription factor , signal transduction , apoptosis , biochemistry , nuclear protein , gene
Bone marrow stem cells (BMSCs) are multipotent stem cells that can regenerate mesenchymal tissues, such as adipose tissue, bone, and muscle. Recent studies have shown that N 6 ‐methyladenosine (m 6 A) methylation, one of the most prevalent epigenetic modifications, is involved in the development process. However, whether it plays roles in BMSC differentiation is still elusive. Here, we found that the deletion of m 6 A “writer” protein methyltransferase‐like (METTL)3 in porcine BMSCs (pBMSCs) could promote adipogenesis and janus kinase (JAK)1 protein expression via an m 6 A‐dependent way. Knockdown of METTL3 decreased mRNA m 6 A levels of JAK1, leading to enhanced YTH m 6 A RNA binding protein 2 (YTHDF2)‐dependent JAK1 mRNA stability. We further demonstrated that JAK1 activated signal transducer and activator of transcription (STAT) 5 through regulation of its phosphorylation to bind to the promoter of CCAAT/enhancer binding protein (C/EBP) β, which could ultimately lead to a modulated adipogenic process. Collectively, our results reveal an orchestrated network linking the m 6 A methylation and JAK1/STAT5/C/EBPβ pathway in pBMSCs adipogenic differentiation. Our findings provide novel insights into the underlying molecular mechanisms of m 6 A modification in the regulation of BMSCs differentiating into adipocytes, which may pave a way to develop more effective therapeutic strategies in stem cell regenerative medicine and the treatment of obesity.—Yao, Y., Bi, Z., Wu, R., Zhao, Y., Liu, Y., Liu, Q., Wang, Y., Wang, X. METTL3 inhibits BMSC adipogenic differentiation by targeting the JAKl/STAT5/C/EBPβ pathway via an m 6 A‐YTHDF2–dependent manner. FASEB J. 33, 7529–7544 (2019). www.fasebj.org