Transcriptional coregulator ZMIZ1 modulates estrogen responses that are essential for healthy endometrial function.
Summary
ZMIZ1, positioned at an ESR1 super-enhancer, is required for endometrial proliferation, decidualization, and proper estrogen/progesterone responses. Uterine Zmiz1 ablation in mice causes infertility, impaired decidual response, reduced PGR expression, and accelerated uterine fibrosis, establishing ZMIZ1 as a key ESR1 coregulator.
Key Findings
- ZMIZ1 colocalizes with an ESR1-binding super-enhancer; mutations observed in endometrial cancer and reduced expression trends in endometriosis.
- Uterine Zmiz1 deletion in mice causes infertility, impaired hormonally induced decidualization, reduced stromal PGR, and accelerated uterine fibrosis.
- Transcriptomics show reduced E2F/CCNA2/FOXM1 signaling; estrogen challenge elicits diminished amplitude of estrogen-responsive genes.
Clinical Implications
Suggests ZMIZ1/ESR1 axis as a potential biomarker and therapeutic target in disorders of endometrial receptivity and function; may inform stratification and targeted modulation of estrogen signaling.
Why It Matters
By defining ZMIZ1 as an estrogen receptor coregulator essential for endometrial function, this work offers mechanistic insight with implications for infertility, endometriosis, and endometrial cancer.
Limitations
- Preclinical nature limits immediate clinical generalizability
- Rescue experiments and therapeutic modulation of ZMIZ1 were not reported
Future Directions
Evaluate ZMIZ1 as a clinical biomarker of endometrial receptivity and test pharmacologic or gene-targeted modulation of the ZMIZ1/ESR1 axis.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- IV - Translational preclinical evidence using conditional knockout mice and human tissue analyses
- Study Design
- OTHER