METTL3 and METTL14-mediated N-methyladenosine modification promotes cell proliferation and invasion in a model of endometriosis.

Research Question: Could METTL3 and METTL14-mediated N-methyladenosine (mA) modification play possible cooperative roles in pathogenesis and progression of endometriosis?

Design: An investigation into mA methylation profiles and the roles of METTL3 and METTL14 in the mA regulation and pathogenesis of endometriosis. The mA methylation and mRNA levels in paired ectopic endometrium and eutopic endometrium were measured using mA-mRNA epitranscriptomic microarrays. The functions of mA methylation in mRNAs were predicted using bioinformatics analysis. The levels of mA methyltransferases were detected using quantitative polymerase chain reaction. The role of METTL3 and METTL14 in endometriosis was explored using eutopic endometrium stromal cells.

Results: The mA methylation levels were decreased in 1312 mRNAs and increased in 518 mRNAs; 1797 mRNAs were increased and 2580 mRNAs were reduced in the ectopic endometrium compared with the eutopic endometrium. Pathway analysis found that the genes with hypo-methylated mA were significantly associated with important pathways in endometriosis, including oestrogen, Hippo, and PI3K-Akt signalling and cell-cell adhesion. Furthermore, METTL3 and METTL14 were downregulated in the ectopic endometrium compared with the eutopic endometrium (P < 0.001). Simultaneous METTL3 and METTL14 knockdown increased cell proliferation and invasion.

Conclusion: Taken together, these data reveal a differential mA epitranscriptomic pattern in endometriosis. The N-methyladenosine modification mediated by METTL3 and METTL14 play a cooperative role in promoting cell proliferation and invasion in a model of endometriosis. Therefore, METTL3 and METTL14 may be a novel treatment target of the disease.