The aberrant
histone methylation patterns contribute to the pathogenesis of
endometriosis (EM). Mixed lineage
leukemia 1 (MLL1), a
histone methyltransferase, is crucial for gene expression by catalyzing the trimethylation of
histone 3
lysine 4 (
H3K4me3) in gene promoter. This study aimed to explore whether MLL1 is involved in EM-related
infertility. The expressions of MLL1 and
H3K4me3 were analyzed in the eutopic endometria from EM women with
infertility (n = 22) and the normal endometria from EM-free women (n = 22). Mouse EM model was established. The MLL1 and
H3K4me3 expression patterns in mice endometria of early pregnancy were also investigated. Immortalized human endometrial stromal cells (iESCs) were cultured and underwent in vitro decidualization. The
chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) was performed to find the target gene of MLL1 during decidual process. Results showed that both MLL1 and
H3K4me3 decreased in the eutopic endometrium from EM patients compared to that in the normal endometrium. During early pregnancy and the decidual process, MLL1 and
H3K4me3 were significantly upregulated in stromal cells. ChIP-seq and ChIP-qPCR found that the
cytochrome c oxidase subunit 4I 2 (COX4I2) was directly targeted by MLL1. The dominance of COX4I2-containing
enzyme induced the expression of
hypoxia-inducible factor-2α (HIF-2α), whose expression in the peri-implantation endometrium is essential for embryo implantation. Further results showed that MLL1 was directly regulated by
progesterone (P4) - P4 receptors (PRs). Our study proved that MLL1 was involved in EM-related
infertility, which may provide a novel approach to treat the nonreceptive endometrium in EM patients.