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METTL3 通过依赖 m6A 的 MIS12 mRNA 稳定性来对抗早衰。

METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA.

机构信息

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.

出版信息

Nucleic Acids Res. 2020 Nov 4;48(19):11083-11096. doi: 10.1093/nar/gkaa816.

DOI:10.1093/nar/gkaa816
PMID:33035345
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7641765/
Abstract

N6-Methyladenosine (m6A) messenger RNA methylation is a well-known epitranscriptional regulatory mechanism affecting central biological processes, but its function in human cellular senescence remains uninvestigated. Here, we found that levels of both m6A RNA methylation and the methyltransferase METTL3 were reduced in prematurely senescent human mesenchymal stem cell (hMSC) models of progeroid syndromes. Transcriptional profiling of m6A modifications further identified MIS12, for which m6A modifications were reduced in both prematurely senescent hMSCs and METTL3-deficient hMSCs. Knockout of METTL3 accelerated hMSC senescence whereas overexpression of METTL3 rescued the senescent phenotypes. Mechanistically, loss of m6A modifications accelerated the turnover and decreased the expression 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. Taken together, we discovered that METTL3 alleviates hMSC senescence through m6A modification-dependent stabilization of the MIS12 transcript, representing a novel epitranscriptional mechanism in premature stem cell senescence.

摘要

N6-甲基腺苷（m6A）信使 RNA 甲基化是一种众所周知的转录后调控机制，影响着核心的生物过程，但它在人类细胞衰老中的功能尚未被研究。在这里，我们发现，早衰的人类间充质干细胞（hMSC）模型中 progeroid 综合征的 m6A RNA 甲基化和甲基转移酶 METTL3 的水平都降低了。m6A 修饰的转录谱进一步鉴定出 MIS12，其 m6A 修饰在早衰的 hMSC 和 METTL3 缺陷的 hMSC 中均减少。METTL3 的敲除加速了 hMSC 的衰老，而过表达 METTL3 则挽救了衰老表型。在机制上，m6A 修饰的缺失加速了 MIS12 mRNA 的周转并降低了其表达，而 MIS12 的敲除则加速了细胞衰老。此外，m6A 阅读器 IGF2BP2 被鉴定为识别和稳定 m6A 修饰的 MIS12 mRNA 的关键因子。总之，我们发现 METTL3 通过 m6A 修饰依赖性稳定 MIS12 转录本来减轻 hMSC 衰老，代表了过早的干细胞衰老中的一种新的转录后机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/c0a0c991649a/gkaa816fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/c4aba962b9a8/gkaa816fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/1e6d34b3fc1e/gkaa816fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/4963c874e412/gkaa816fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/b4f15f519a2d/gkaa816fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/524b66d7a724/gkaa816fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/c0a0c991649a/gkaa816fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/c4aba962b9a8/gkaa816fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/1e6d34b3fc1e/gkaa816fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/4963c874e412/gkaa816fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/b4f15f519a2d/gkaa816fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/524b66d7a724/gkaa816fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c9d/7641765/c0a0c991649a/gkaa816fig6.jpg

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