METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPβ pathway via an m6A-YTHDF2-dependent manner

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) beta, 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/EBP beta 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 JAK1/STAT5/C/EBP beta pathway via an m(6)A-YTHDF2-dependent manner.