Decreased Expression of EZH2 in Granulosa Cells Contributes to Endometriosis-Associated Infertility by Targeting IL-1R2

Abstract

The mechanism by which endometriosis, a common gynecological disease characterized by chronic pelvic pain and infertility, causes infertility remains elusive. Luteinized unruptured follicle syndrome, the most common type of ovulatory dysfunction, is a cause of endometriosis-associated infertility involving reduced numbers of retrieved and mature oocytes. Ovulation is controlled by luteinizing hormone and paracrine signals produced within the follicle microenvironment. Generally, interleukin (IL)-1β is elevated in endometriosis follicular fluid, whereby it amplifies ovulation signals by activating extracellular-regulated kinase 1/2 and CCAAT/enhancer binding protein β pathways. However, this amplification of ovulation by IL-1β does not occur in patients with endometriosis. To illuminate the mechanism of ovulatory dysfunction in endometriosis, we analyzed the impact of oxidative stress and IL-1β expression in endometriosis follicles. We found that oxidative stress decreased EZH2 expression and reduced H3K27Me3 levels in endometriosis ovarian granulosa cells (GCs). Selective Ezh2 depletion in mice ovarian GCs reduced fertility by disturbing cumulus-oocyte complex expansion and reducing epidermal growth factor-like factor expression. Gene expression and H3K27Me3 ChIP-sequencing of GCs revealed IL-1 receptor 2 (IL-1R2), a high-affinity IL-1β-receptor that suppresses IL-1β-mediated inflammatory cascades during ovulation, as a crucial target gene of the EZH2-H3K27Me3 axis. Moreover, IL-1β addition did not restore ovulation upon Ezh2 knockdown, indicating a vital function of IL-1R2 in endometriosis. Thus, our findings show that reducing EZH2 and H3K27Me3 in GCs suppressed ovulatory signals by increasing IL-1R2 expression, which may ultimately contribute to endometriosis-associated infertility.

The involvement of RNA N6‐methyladenosine and histone methylation modification in decidualization and endometriosis‐associated infertility

“…EZH2 and H3K27Me3 were highly expressed in the heterotopic endometrial lesions of EM patients compared with those in eutopic and control endometria 29,58–60 . Moreover, we demonstrated in previous research that decreased EZH2 expression and reduced H3K27Me3 levels in EM ovarian granulosa cells can disturb ovulation and lead to EM‐associated infertility 61 . However, no study has explored the roles of EZH2 in EM decidualization.…”

“… 29 , 58 , 59 , 60 Moreover, we demonstrated in previous research that decreased EZH2 expression and reduced H3K27Me3 levels in EM ovarian granulosa cells can disturb ovulation and lead to EM‐associated infertility. 61 However, no study has explored the roles of EZH2 in EM decidualization. Decidualization failure is associated with a disturbance of oestrogen and progesterone, abnormal inflammation, imbalanced expression of multiple endocrine, paracrine and autocrine modulators in the endometrium, epigenetic modifiers and chromatin modifications.…”

Decreased oocyte quality in patients with endometriosis is closely related to abnormal granulosa cells

“…Oxidative stress may hinder ovulation in addition to lowering oocyte quality. Lin discovered that oxidative stress might decrease the expression of the histone-lysine N-methyltransferase EZH2 and the level of lysine 27 of the histone H3 protein in GCs while increasing the expression of Interleukin-1 receptor type 2 to suppress ovulation signals ( 77 ).…”

“…The aberrant follicular development in EMS patients is linked to a defective FSH signaling pathway operating on GCs, and EMS patients respond to FSH less effectively during ovulation induction ( 78 ). Although FSHR and cytochrome P450 family 19 subfamily A member 1(CYP19A1) expression levels are lower in GCs from EMS patients ( 77 ), it is unknown how EMS specifically changes FSHR signaling. According to other research ( 79 , 80 ), the levels of estrogen and testosterone in the follicular fluid of patients with EMS are lower than those of patients without EMS, but the amount of progesterone is higher.…”

Elevated IL-8/TNF-α in follicle fluid of infertile women with endometriosis decrease LHCGR expression in cumulus cells

“…In granulosa cells of the developing follicle, FSH activates several signaling pathways including phosphatidylinositol 3-kinase/AKT and inhibits phosphatidylinositol SMAD2/3 to express the LH receptor (27,28). Currently, granulosa cells obtained from immature follicles of female mice or rats are used to study the molecular mechanism of LH receptor expression (29,30). However, due to the estrous cycle, it is di cult to ensure that the granulosa cells used in experiments are at an immature stage when LH receptors are almost not expressed (31).…”