METTL3-dependent m6A methylation facilitates uterine receptivity and female fertility via balancing estrogen and progesterone signaling

Abstract

Infertility is a worldwide reproductive health problem and there are still many unknown etiologies of infertility. In recent years, increasing evidence emerged and confirmed that epigenetic regulation played a leading role in reproduction. However, the function of m6A modification in infertility remains unknown. Here we report that METTL3-dependent m6A methylation plays an essential role in female fertility via balancing the estrogen and progesterone signaling. Analysis of GEO datasets reveal a significant downregulation of METTL3 expression in the uterus of infertile women with endometriosis or recurrent implantation failure. Conditional deletion of Mettl3 in female reproductive tract by using a Pgr-Cre driver results in infertility due to compromised uterine endometrium receptivity and decidualization. m6A-seq analysis of the uterus identifies the 3’UTR of several estrogen-responsive genes with METTL3-dependent m6A modification, like Elf3 and Celsr2, whose mRNAs become more stable upon Mettl3 depletion. However, the decreased expression levels of PR and its target genes, including Myc, in the endometrium of Mettl3 cKO mice indicate a deficiency in progesterone responsiveness. In vitro, Myc overexpression could partially compensate for uterine decidualization failure caused by Mettl3 deficiency. Collectively, this study reveals the role of METTL3-dependent m6A modification in female fertility and provides insight into the pathology of infertility and pregnancy management.

Basic Research Advances in China on Embryo Implantation, Placentation, and Parturition

“…19 The significance of m 6 A modification in embryo implantation remains unclear. In recent studies, Zheng et al 20 and Wan et al 21 revealed the m 6 A-mediated mechanisms for ensuring normal progesterone and estrogen signaling during embryo implantation. Uterine-specific deletion of the m 6 A writer METTL3 culminates in implantation failure due to preimplantation embryo loss and compromised uterine receptivity.…”

“…Specifically, m 6 A-seq analysis identified m 6 A modifications in the 3′ untranslated region of several estrogen-responsive genes, mRNAs of which exhibited increased stability upon METTL3 depletion. 21 In addition to posttranscriptional regulation, steroid nuclear receptor activities are also regulated by posttranslational modifications, such as phosphorylation and ubiquitination. 22,23 Tang et al 24 recently reported that uterine deficiency of p38α-impaired uterine receptivity ascribed to reduced PR protein levels and reduced progesterone responsiveness in the uterine stroma.…”

“…In recent studies, Zheng et al 20 . and Wan et al 21 . revealed the m 6 A-mediated mechanisms for ensuring normal progesterone and estrogen signaling during embryo implantation.…”

“…Loss of m 6 A modifications causes estrogen dominance and progesterone resistance. Specifically, m 6 A-seq analysis identified m 6 A modifications in the 3′ untranslated region of several estrogen-responsive genes, mRNAs of which exhibited increased stability upon METTL3 depletion 21 . In addition to posttranscriptional regulation, steroid nuclear receptor activities are also regulated by posttranslational modifications, such as phosphorylation and ubiquitination 22,23 .…”

The functions and mechanisms of RNA modification in prostate: Current status and future perspectives

“…METTL3 directly regulates the expression levels of classical oncogenes or tumor suppressor genes, reflecting its important role in tumor progression. It also exerts methyltransferase activity, guiding the transcription of MYC mRNA and promoting the progression of PCa (Wan et al, 2023). Furthermore, the cancer-promoting factor METTL3 and its upstream cofactor YTH domain family 2 protein (YTHDF2), were identified as the key "writer" and "reader" of m6A modification, facilitating mRNA degradation of tumor suppressor lipid phosphatase and NK3 homeobox 1 and promoting the proliferation and migration of PCa cells.…”