N⁶-methyladenine (m⁶A) is the most abundant epitranscriptomic modification on messenger RNA (mRNA). The establishment, erasure, and recognition of m⁶A are dynamically regulated by m⁶A methyltransferases (writers), demethylases (erasers) and binding proteins (readers), respectively. It has been well known that m⁶A modifications play crucial roles in regulating splicing, transport, stability, and translation of target RNAs. Emerging evidence has shown that m⁶A modifications impinge on central biological processes such as stemness maintenance and differentiation, adipogenesis, and spermatogenesis and are implicated in pathological processes underlying obesity, infertility, diabetes, neuronal disorders, aberrant immune signaling and cancers. However, the role of m⁶A RNA modifications in regulating stem cell senescence remains largely unknown.

Recently, scientists from the Institute of Zoology and Beijing Institute of Genomics of the Chinese Academy of Sciences have collaborated jointly to unveil a novel mechanism of METTL3 as well as m⁶A in regulating human stem cell senescence. This study entitled “METTL3 counteracts premature aging via m⁶A-dependent stabilization of MIS12 mRNA” was published online in Nucleic Acids Research on October 9th, 2020. Using including Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS), researchers explored the function of m⁶A and its core methyltransferase METTL3 during human stem cell aging and revealed that MIS12 functions as a downstream factor of METTL3/m⁶A in regulating hMSC senescence.

In the study, researchers first found that the levels of both m⁶A RNA methylations and its METTL3 were reduced during human stem cell aging. Knockout of METTL3 accelerated stem cell senescence whereas overexpression of METTL3 rescued cellular senescence phenotypes. Transcriptional profiling of m⁶A modifications further identified MIS12, a cell cycle regulator, of which m⁶A modifications were reduced in both hMSCs and METTL3-deficient hMSCs. Mechanistically, loss of m⁶A modifications decreased the expression and accelerated the turnover of MIS12 mRNA while knockout of MIS12 accelerated cellular senescence. Furthermore, m⁶A reader IGF2BP2 was identified as a key player in recognizing and stabilizing m⁶A-modified MIS12 mRNA; knockdown of IGF2BP2 also accelerated senescence in human stem cells.

Taken together, this study puts forth a regulatory model in which METTL3 and m⁶A modifications alleviate hMSC senescence through IGF2BP2-mediated enhancement of MIS12 mRNA stability. The existence of a direct molecular connection between MIS12 expression and its m⁶A level suggests the manipulation of m⁶A modifications or its core methyltransferase METTL3 as potential strategies for cellular rejuvenation. This work sheds light on the poorly understood molecular mechanism of m⁶A in aging and identifies METLL3 and MIS12 as potential novel biomarkers and therapeutic targets for aging-associated disorders.

Figure. A model illustrating the protective role of METTL3/m⁶A in alleviating hMSC senescence through IGF2BP2-mediated enhancement of MIS12 mRNA stability.

Link:

https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkaa816/5920440

(Contact: Liu Guanghui, ghliu@ioz.ac.cn)