Endometrial Epithelial ARID1A Is Required for Uterine Immune Homeostasis during Early Pregnancy

A growing body of work suggests epigenetic dysregulation contributes to endometriosis pathophysiology and female infertility. The chromatin remodeling complex subunit AT-rich interaction domain 1A (ARID1A) must be properly expressed to maintain normal uterine function. Endometrial epithelial ARID1A is indispensable for pregnancy establishment in mice through regulation of endometrial gland function; however, ARID1A expression is decreased in infertile women with endometriosis. We hypothesized that ARID1A performs critical operations in the endometrial epithelium necessary for fertility besides maintaining gland function. To identify alterations in uterine gene expression resulting from loss of epithelial ARID1A, we performed RNA-sequencing analysis on pre-implantation uteri from Ltf(iCre/+)Arid1a(f/f) and control mice. Differential expression analysis identified 4181 differentially expressed genes enriched for immune-related ingenuity canonical pathways including agranulocyte adhesion and diapedesis and natural killer cell signaling. RT-qPCR confirmed an increase in pro-inflammatory cytokine and macrophage-related gene expression but a decrease in natural killer cell signaling. Immunostaining confirmed a uterus-specific increase in macrophage infiltration. Flow cytometry delineated an increase in inflammatory macrophages and a decrease in uterine dendritic cells in Ltf(iCre/+)Arid1a(f/f) uteri. These findings demonstrate a role for endometrial epithelial ARID1A in suppressing inflammation and maintaining uterine immune homeostasis, which are required for successful pregnancy and gynecological health.

Automated summary

A growing body of work suggests that epigenetic dysregulation is involved in the pathophysiology of endometriosis and female infertility. This study focuses on the chromatin remodeling complex subunit ARID1A and its role in maintaining normal uterine function. The researchers found that ARID1A is decreased in infertile women with endometriosis and hypothesized that it is involved in critical operations in the endometrial epithelium necessary for fertility. Through RNA-sequencing analysis on pre-implantation uteri from mice, they discovered alterations in immune-related gene expression resulting from loss of epithelial ARID1A. These findings demonstrate the importance of endometrial epithelial ARID1A in suppressing inflammation and maintaining uterine immune homeostasis for successful pregnancy and gynecological health.