METTL3 and METTL14-mediated N6-methyladenosine modification promotes cell proliferation and invasion in a model of endometriosis

Abstract

Research question: Could METTL3 and METTL14-mediated N⁶-methyladenosine (m⁶A) modification play possible cooperative roles in pathogenesis and progression of endometriosis?

Design: An investigation into m⁶A methylation profiles and the roles of METTL3 and METTL14 in the m⁶A regulation and pathogenesis of endometriosis. The m⁶A methylation and mRNA levels in paired ectopic endometrium and eutopic endometrium were measured using m⁶A-mRNA epitranscriptomic microarrays. The functions of m⁶A methylation in mRNAs were predicted using bioinformatics analysis. The levels of m⁶A 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 m⁶A 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 m⁶A 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 m⁶A epitranscriptomic pattern in endometriosis. The N⁶-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.

Keywords: Endometriosis; METTL14; METTL3; N6-methyladenosine; mRNAs.