GSE129783
ARID1A and PI3-Kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion [Mouse_ATAC-seq]
ARID1A and PI3-Kinase (PI3K) pathway alterations are common in neoplasms originating from the uterine endometrium. Here we show that monoallelic loss of ARID1A in the mouse endometrial epithelium is sufficient for vaginal bleeding when combined with PI3K activation. Sorted mutant epithelial cells display gene expression and promoter chromatin signatures associated with epithelial-to-mesenchymal transition (EMT). We further show that ARID1A is bound to promoters with open chromatin, but ARID1A loss leads to increased promoter chromatin accessibility and the expression of EMT genes. PI3K activation partially rescues the mesenchymal phenotypes driven by ARID1A loss through antagonism of ARID1A target gene expression, resulting in partial EMT and invasion. We propose that ARID1A normally maintains endometrial epithelial cell identity by repressing mesenchymal cell fates, and that coexistent ARID1A and PI3K mutations promote epithelial transdifferentiation and collective invasion. Broadly, our findings support a role for collective epithelial invasion in the spread of abnormal endometrial tissue. Overall design: EPCAM+ endometrial epithelial cells from hyperplastic LtfCre0/+; (Gt)Rosa26Pik3ca*H1047R; Arid1afl/fl, LtfCre0/+; (Gt)Rosa26Pik3ca*H1047R; Arid1afl/+, LtfCre0/+; (Gt)Rosa26Pik3ca*H1047R; Arid1afl/V1068G, and healthy control wild-type CD-1 mice were purified and assayed for genome-wide chromatin accessibility via ATAC. Mature female mice were euthanized prior to vaginal bleeding.