The histone methyltransferase EZH2 is required for normal uterine development and function in mice†

Area of Science:

• Reproductive Biology
• Epigenetics
• Developmental Biology

Background:

• Enhancer of zeste homolog 2 (EZH2) is a key enzyme in gene silencing via histone methylation (H3K27me3).
• EZH2 plays a role in estrogen-mediated epigenetic effects and is implicated in uterine development and disease.

Purpose of the Study:

• To investigate the expression, regulation, and functional role of EZH2 in uterine development and function.
• To determine the impact of EZH2 loss on uterine histology, proliferation, and fertility.

Main Methods:

• Examined EZH2 expression in mouse uteri during development and in response to hormones (estradiol, progesterone).
• Created a conditional knockout mouse model (Ezh2cKO) to specifically delete EZH2 in progesterone receptor-expressing tissues.
• Analyzed uterine and mammary gland phenotypes, including histology, proliferation markers, and fertility in Ezh2cKO mice.

Main Results:

• Neonatal uterine EZH2 expression is independent of estrogen receptor 1 but is regulated by estradiol and progesterone in adults.
• Ezh2cKO uteri exhibited reduced H3K27me3, increased size, cystic endometrial hyperplasia, and ovary-independent epithelial proliferation.
• Ezh2cKO females showed initial subfertility progressing to infertility and inhibited mammary gland development.

Conclusions:

• Uterine EZH2 expression is developmentally and hormonally controlled.
• Loss of EZH2 results in aberrant uterine epithelial proliferation, hypertrophy, and hyperplasia, underscoring its critical role in uterine function.
• EZH2 is essential for normal uterine development, tissue homeostasis, and female fertility.