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Open Access 01-12-2023 | Endometriosis | Research

METTL3-mediated m6A modification of SIRT1 mRNA inhibits progression of endometriosis by cellular senescence enhancing

Authors: Xiaotong Wang, Jing Wang, Xibo Zhao, Han Wu, Jixin Li, Yan Cheng, Qiuyan Guo, Xuejiao Cao, Tian Liang, Liyuan Sun, Guangmei Zhang

Published in: Journal of Translational Medicine | Issue 1/2023

Abstract

Background

Endometriosis (EMs), the ectopic planting of functional endometrium outside of the uterus, is a leading cause of infertility and pelvic pain. As a fundamental mRNA modification, N6-methyladenosine (m6A) participates in various pathological processes. However, the role of m6A RNA modification in endometriosis remains unclear. The present study explores METTL3-mediated m6A modification and the mechanisms involved in endometriosis.

Methods

The dominant m6A regulators in EMs were analysed using RT‒PCR. Candidate targets and possible mechanisms of METTL3 were assessed by m6A-mRNA epitranscriptomic microarray and RNA sequencing. A primary ESCs model was employed to verify the effect of METTL3 on m6A modification of SIRT1 mRNA, and the mechanism was elucidated by RT‒PCR, Western blotting, MeRIP, and RIP assays. CCK-8 viability assays, Transwell invasion assays, EdU proliferation assays, wound healing migration assays, and senescence-associated β-galactosidase staining were performed to illuminate the potential biological mechanism of METTL3 and SIRT1 in ESCs in vitro. An in vivo PgrCre/ + METTL3 −/− female homozygous mouse model and a nude mouse xenograft model were employed to further investigate the physiologic consequences of METTL3-mediated m6A alteration on EMs.

Results

Our data show that decreased METTL3 expression significantly downregulates m6A RNA methylation levels in ESCs. Silencing m6A modifications mediated by METTL3 accelerates ESCs viability, proliferation, migration, and invasion in vitro. The m6A reader protein YTHDF2 binds to m6A modifications to induce the degradation of SIRT1 mRNA. SIRT1/FOXO3a signalling pathway activation is subsequently inhibited, promoting the cellular senescence of ESCs and inhibiting the ectopic implantation of ESCs in vitro and in vivo.

Conclusions

Our findings demonstrate that METTL3-mediated m6A methylation epigenetically regulates the ectopic implantation of ESCs, resulting in the progression of endometriosis. Our study establishes METTL3-YTHDF2-SIRT1/FOXO3a as a critical axis and potential mechanism in endometriosis.

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Title: METTL3-mediated m6A modification of SIRT1 mRNA inhibits progression of endometriosis by cellular senescence enhancing
Authors: Xiaotong Wang
Jing Wang
Xibo Zhao
Han Wu
Jixin Li
Yan Cheng
Qiuyan Guo
Xuejiao Cao
Tian Liang
Liyuan Sun
Guangmei Zhang
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Endometriosis
Epigenetics
Published in: Journal of Translational Medicine / Issue 1/2023
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-023-04209-0

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