YTH Domain Family 2 Promotes Tubal Factor Infertility through Reducing H3K4me1 Methylation of CYLD by KMT2D

Tubal factor infertility (TFI) is one of the most common causes of infertility. TFI may be caused by impaired muscle contractions and ciliary beats. Further study on the molecular mechanism of tubal inflammation and cilia beat frequency is of great clinical significance for improving and preventing TFI. In this study, we found that compared with the Control group, the expression of histone-lysine N-methyltransferase 2D (KMT2D) in LPS-induced rat tubal epithelial cells was decreased. Oe-KMT2D promoted KMT2D expression in LPS-induced rat tubal epithelial cells, increased cell viability and ciliary beat frequency, and inhibited IL-1β, IL-6, IL-8, TNF-α, and MPO levels. Si-KMT2D inhibited the enrichment of KMT2D and H3K4me1 in the cylindromatosis (CYLD) promoter. Si-CYLD reversed oe-KMT2D effect on LPS-stimulated tubal epithelial cells. RIP results showed that YTH domain family 2 (YTHDF2) inhibited KMT2D level by binding to KMT2D mRNA. Si-YTHDF2 upregulated KMT2D expression and CYLD in LPS-induced tubal epithelial cells, increased cell viability and ciliary beat frequency, and inhibited YTHDF2, IL-1β, IL-6, IL-8, TNF-α, and MPO levels. Si-KMT2D interrupted si-YTHDF2 effect on LPS-induced rat tubal epithelial cells. In addition, si-YTHDF2 promoted KMT2D and CYLD expression in tubal tissue of TFI rats, increased the pregnancy rate and live birth rate, improved the degree of uterine and tubal lesions, and inhibited the serum levels of IL-1β, IL-6, IL-8, TNF-α, and MPO. Si-KMT2D reversed si-YTHDF2 effect on TFI rats. Knockdown YTHDF2 alleviated TFI in vivo by promoting KMT2D/CYLD axis, which might provide a new molecular target for clinical treatment of TFI.