Yu, Shen, Liu, Ming, Zhu, Chu, Lin (2019) The m6A methyltransferase METTL3 cooperates with demethylase ALKBH5 to regulate osteogenic differentiation through NF-κB signaling Molecular and cellular biochemistry ()

Abstract

As a m6A methylation modifier, METTL3 is functionally involved in various biological processes. Nevertheless, the role of METTL3 in osteogenesis is not determined up to date. In the current study, METTL3 is identified as a crucial regulator in the progression of osteogenic differentiation. Loss of METTL3 significantly augments calcium deposition and enhances alkaline phosphatase activity of mesenchymal stem cells, uncovering an inhibitory role of METTL3 in osteogenesis. More importantly, the underlying molecular basis by which METTL3 regulates osteogenesis is illustrated. We find that METTL3 positively regulates expression of MYD88, a critical upstream regulator of NF-κB signaling, by facilitating m6A methylation modification to MYD88-RNA, subsequently inducing the activation of NF-κB which is widely regarded as a repressor of osteogenesis and therefore suppressing osteogenic progression. Moreover, the METTL3-mediated m6A methylation is found to be dynamically reversed by the demethylase ALKBH5. In summary, this study highlights the functional importance of METTL3 in osteogenic differentiation and METTL3 may serve as a promising molecular target in regenerative medicine, as well as in the field of bone tissue engineering.

作为m6A甲基化修饰剂,METTL3在功能上涉及各种生物过程。然而,尚未确定METTL3在成骨中的作用。在当前的研究中,METTL3被确定为成骨分化过程中的关键调节剂。 METTL3的缺失显着增加了间充质干细胞的钙沉积并增强了碱性磷酸酶活性,从而揭示了METTL3在成骨中的抑制作用。更重要的是,说明了METTL3调节成骨的潜在分子基础。我们发现,METTL3通过促进对MYD88-RNA的m6A甲基化修饰,进而诱导NF-κB的活化而正调控MY-88的表达,MYD88是NF-κB信号的关键上游调节剂,随后诱导NF-κB的活化,而NF-κB被普遍认为是成骨抑制因子,因此抑制成骨进展。此外,发现METTL3介导的m6A甲基化被脱甲基酶ALKBH5动态逆转。总而言之,这项研究强调了METTL3在成骨分化中的功能重要性,并且METTL3可能在再生医学以及骨组织工程领域中成为有希望的分子靶标。

Links

http://www.ncbi.nlm.nih.gov/pubmed/31643040
http://dx.doi.org/10.1007/s11010-019-03641-5

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