Endometrial aging is accompanied by H3K27ac and PGR loss.
Summary
This translational study links endometrial aging to loss of H3K27ac and reduced progesterone receptor expression, impairing receptivity. Multi-system evidence from human cohorts, stromal cell perturbations, and a mouse model supports H3K27ac as a regulator of PGR and fertility.
Key Findings
- Middle-aged patients showed worse pregnancy outcomes even after excluding aneuploid embryos, implicating endometrial aging.
- Mid-secretory endometrium from middle-aged patients exhibited H3K27ac loss linked to reduced receptivity.
- CRISPR-mediated H3K27ac elimination in young human endometrial stromal cells reduced PGR expression.
- Mouse models validated the association between H3K27ac/PGR loss and uterine aging.
Clinical Implications
Potential for endometrial aging biomarkers (H3K27ac/PGR) to guide cycle selection in ART and for testing epigenetic therapies to improve receptivity in older patients.
Why It Matters
It identifies a specific epigenetic mark, H3K27ac, as a mechanistic link between endometrial aging and receptivity via PGR, opening avenues for biomarker development and epigenetic interventions in ART.
Limitations
- Omics sample sizes and batch effects are not fully detailed, and causality in humans remains inferential.
- No interventional human data to show reversibility of H3K27ac loss or clinical benefit.
Future Directions
Develop validated endometrial aging biomarkers (H3K27ac/PGR), test epigenetic modulators to restore receptivity, and conduct prospective ART trials stratified by epigenetic age.
Study Information
- Study Type
- Case-control study
- Research Domain
- Pathophysiology
- Evidence Level
- III - Non-randomized comparative human data with mechanistic validation in vitro and in vivo
- Study Design
- OTHER