NDLI: Increased METTL3-mediated m6A methylation inhibits embryo implantation by repressing HOXA10 expression in recurrent implantation failure

Content Provider	Springer Nature : BioMed Central
Author	Xue, Pingping Zhou, Wenbo Fan, Wenqiang Jiang, Jianya Kong, Chengcai Zhou, Wei Zhou, Jianmei Huang, Xiaoyang Yang, Haiyan Han, Qian Zhang, Bin Xu, Lingyun Yu, Bin Chen, Li
Abstract	Background Recurrent implantation failure (RIF) is a major limitation of assisted reproductive technology, which is associated with impaired endometrial receptivity. Although N6-methyladenosine (m6A) has been demonstrated to be involved in various biological processes, its potential role in the endometrium of women with RIF has been poorly studied. Methods Global m6A levels and major m6A methyltransferases/demethylases mRNA levels in mid-secretory endometrium from normal and RIF women were examined by colorimetric m6A quantification strategy and quantitative real-time PCR, respectively. The effects of METTL3-mediated m6A modification on embryo attachment were evaluated by an vitro model of a confluent monolayer of Ishikawa cells co-cultured with BeWo spheroids, and the expression levels of homeo box A10 (HOXA10, a well-characterized marker of endometrial receptivity) and its downstream targets were evaluated by quantitative real-time PCR and Western blotting in METTL3-overexpressing Ishikawa cells. The molecular mechanism for METTL3 regulating HOXA10 expression was determined by methylated RNA immunoprecipitation assay and transcription inhibition assay. Results Global m6A methylation and METTL3 expression were significantly increased in the endometrial tissues from women with RIF compared with the controls. Overexpression of METTL3 in Ishikawa cells significantly decreased the ration of BeWo spheroid attachment, and inhibited HOXA10 expression with downstream decreased β3-integrin and increased empty spiracles homeobox 2 expression. METTL3 catalyzed the m6A methylation of HOXA10 mRNA and contributed to its decay with shortened half-life. Enforced expression of HOXA10 in Ishikawa cells effectively rescued the impairment of METTL3 on the embryo attachment in vitro. Conclusion Increased METTL3-mediated m6A modification represents an adverse impact on embryo implantation by inhibiting HOXA10 expression, contributing to the pathogenesis of RIF.
Related Links	https://rbej.biomedcentral.com/counter/pdf/10.1186/s12958-021-00872-4.pdf
Ending Page	11
Page Count	11
Starting Page	1
File Format	HTM / HTML
ISSN	14777827
DOI	10.1186/s12958-021-00872-4
Journal	Reproductive Biology and Endocrinology
Issue Number	1
Volume Number	19
Language	English
Publisher	BioMed Central
Publisher Date	2021-12-14
Access Restriction	Open
Subject Keyword	Reproductive Medicine Endocrinology METTL3 m6A methylation HOXA10 embryo implantation recurrent implantation failure
Content Type	Text
Resource Type	Article
Subject	Endocrinology Obstetrics and Gynecology Developmental Biology Reproductive Medicine
Journal Impact Factor	4.2/2023
5-Year Journal Impact Factor	5.3/2023

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