Language
English
Publication Date
12-1-2025
Journal
Journal of Clinical Investigation
DOI
10.1172/JCI193212
PMID
41321316
PMCID
PMC12646675
PubMedCentral® Posted Date
12-1-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Estrogen is a critical regulator of endometrial health. Aberrant estrogen stimulation can result in infertility, endometrial cancer, and endometriosis. Here, we identified Zinc Finger MIZ-Type Containing 1 (Zmiz1) as a coregulator of uterine estrogen signaling. ZMIZ1 is colocalized with an estrogen receptor α–binding (ESR1-binding) super enhancer. ZMIZ1 mutations are found in endometrial cancer and its RNA levels trend toward reduction in endometrium of patients with endometriosis. ZMIZ1 is dynamically expressed in human endometrial tissues during the menstrual cycle. Disrupting ZMIZ1 in cultured human endometrial stromal cells resulted in impaired cell proliferation and decidual differentiation. Ablation of Zmiz1 using the PgrCre mouse (Zmiz1d/d) resulted in infertility and accelerated age-dependent uterine fibrosis. Zmiz1d/d mice showed reduced ovulation and progesterone levels while maintaining normal serum prolactin during pregnancy. Uteri of Zmiz1d/d mice were unable to undergo a hormonally induced decidual response, had decreased expression of stromal progesterone receptor (PGR) and decreased stromal and epithelial cell proliferation. Analysis of the transcriptome of Zmiz1d/d mouse uteri showed decreased E2F, CCNA2, and FOXM1 signaling. Challenging ovariectomized Zmiz1d/d mice with estrogen resulted in a decreased amplitude of some estrogen-regulated gene responses. Our findings demonstrate the importance of ZMIZ1 as an ESR1 coregulator in uterine biology and pathology.
Keywords
Female, Animals, Mice, Humans, Estrogens, Endometrium, Estrogen Receptor alpha, Transcription Factors, Mice, Knockout, Decidua, Signal Transduction, Pregnancy, Cell Proliferation, Stromal Cells, Receptors, Progesterone, Endocrinology, Reproductive biology, Reproductive biochemistry, Sex hormones, Transcription
Published Open-Access
yes
Recommended Citation
Hewitt, Sylvia C; Orellana, Frank; Marquardt, Ryan M; et al., "Transcriptional Coregulator ZMIZ1 Modulates Estrogen Responses That Are Essential for Healthy Endometrial Function" (2025). Faculty and Staff Publications. 5604.
https://digitalcommons.library.tmc.edu/baylor_docs/5604
Graphical Abstract
Included in
Allergy and Immunology Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Endocrinology, Diabetes, and Metabolism Commons, Pathology Commons