METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPβ pathway an mA-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 -methyladenosine (mA) 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 mA "writer" protein methyltransferase-like (METTL)3 in porcine BMSCs (pBMSCs) could promote adipogenesis and janus kinase (JAK)1 protein expression an mA-dependent way. Knockdown of METTL3 decreased mRNA mA levels of JAK1, leading to enhanced YTH mA 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 mA methylation and JAK1/STAT5/C/EBPβ pathway in pBMSCs adipogenic differentiation. Our findings provide novel insights into the underlying molecular mechanisms of mA 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/EBPβ pathway an mA-YTHDF2-dependent manner.