The Novel Transcriptional Co-regulator, ZMIZ1, Modulates Hormone Responses that are Essential for Optimal Endometrial Health [H1644_and_THESC-RNAseq]

The endometrial expression and activity of the transcriptional co-regulator, Zinc Finger MIZ-Type Containing 1 (Zmiz1), that is co-localized with a mouse uterine estrogen receptor α (ERα)-binding super-enhancer, has not yet been evaluated. In human endometrial biopsy samples ZMIZ1 transcript and protein is dynamically expressed during the menstrual cycle. ZMIZ1 mutations are associated with some uterine tumors and ZMIZ1 RNA levels are increased in endometrium from individuals with endometriosis. Disrupting ZMIZ1 in cultured human endometrial stromal cells or in mouse uterus prevented hormone-dependent proliferation of epithelial and stromal cells as well as decidual differentiation of stroma cells, triggering sterility. Additionally, aging-dependent fibrosis was accelerated in Zmiz1-targeted mouse uterus. Notably, ZMIZ1 deletion impacted expression of stromal cell progesterone receptor (PGR), which is essential for decidual transformation. ZMIZ1 and ERα were co-localized in nuclei of mouse uterine cells, and E2F, CCNA2 and FOXM1 signaling were all decreased when ZMIZ1 was targeted, which likely underlies reduced cell cycle progression. Transcriptomic analyses revealed that loss of ZMIZ1 alters the amplitude of estrogen regulated gene responses, indicating ZMIZ1 fine-tunes endometrial cell signals needed for optimal functioning. Our findings demonstrate the importance of ZMIZ1 as an ERα co-regulator in uterine biology and pathology.