ARID1A Is Essential for Endometrial Function during Early Pregnancy

Abstract

AT-rich interactive domain 1A gene (ARID1A) loss is a frequent event in endometriosis-associated ovarian carcinomas. Endometriosis is a disease in which tissue that normally grows inside the uterus grows outside the uterus, and 50% of women with endometriosis are infertile. ARID1A protein levels were significantly lower in the eutopic endometrium of women with endometriosis compared to women without endometriosis. However, an understanding of the physiological effects of ARID1A loss remains quite poor, and the function of Arid1a in the female reproductive tract has remained elusive. In order to understand the role of Arid1a in the uterus, we have generated mice with conditional ablation of Arid1a in the PGR positive cells (Pgr cre/+ Arid1a f/f; Arid1a d/d). Ovarian function and uterine development of Arid1a d/d mice were normal. However, Arid1a d/d mice were sterile due to defective embryo implantation and decidualization. The epithelial proliferation was significantly increased in Arid1a d/d mice compared to control mice. Enhanced epithelial estrogen activity and reduced epithelial PGR expression, which impedes maturation of the receptive uterus, was observed in Arid1a d/d mice at the peri-implantation period. The microarray analysis revealed that ARID1A represses the genes related to cell cycle and DNA replication. We showed that ARID1A positively regulates Klf15 expression with PGR to inhibit epithelial proliferation at peri-implantation. Our results suggest that Arid1a has a critical role in modulating epithelial proliferation which is a critical requisite for fertility. This finding provides a new signaling pathway for steroid hormone regulation in female reproductive biology and furthers our understanding of the molecular mechanisms that underlie dysregulation of hormonal signaling in human reproductive disorders such as endometriosis.

KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance

“…ChIP assays were performed as previously described 80 . Briefly, 100 μg of chromatin from Ishkawa cells were immunoprecipitated by 4 μg of antibodies against BCL6 (BD Pharmingen).…”

Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why

“…Rel-A inhibits progesterone receptor via the PR promoter (80) and therefore further contributes to progesterone resistance. ARID1A, an anti-inflammatory protein that is often mutated in ovarian and breast cancers (81, 82), is down-regulated in endometriosis (83), and appears to be a key regulator of the inflammatory response seen in this disease, by blocking Rel-A action on cytokine expression (82). Inflammatory responses are also exaggerated by the loss of other regulatory proteins including protein-inhibitor of STAT3 (PIAS3), which we recently reported was reduced in the endometrium of women with endometriosis (84).…”

New models of lipopolysaccharide‐induced implantation loss reveal insights into the inflammatory response

“…Gross examination of uterine histology at 5.5 dpc in LPS-treated mice revealed slightly smaller implantation sites and incomplete closure of the luminal epithelium compared to control mice ( Figure 1E). [26][27][28] The process of murine decidualization is characterized by pronounced stromal cell proliferation. Expression of Areg, a member of the epidermal growth factor family expressed in the luminal epithelial cells at the time of implantation, was induced in the uterus of control mice but not in the uterus of mice exposed to LPS.…”