Mice lacking uterine enhancer of zeste homolog 2 have transcriptomic changes associated with uterine epithelial proliferation

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that suppresses gene expression. Previously, we developed a conditional null model where EZH2 is knocked out in uterus. Deletion of uterine EZH2 increased proliferation of luminal and glandular epithelial cells. Herein, we used RNA-Seq in wild-type (WT) and EZH2 conditional knockout (<i>Ezh2</i>cKO) uteri to obtain mechanistic insights into the gene expression changes that underpin the pathogenesis observed in these mice. Ovariectomized adult <i>Ezh2</i>cKO mice were treated with vehicle (V) or 17β-estradiol (E2; 1 ng/g). Uteri were collected at postnatal day (PND) 75 for RNA-Seq or immunostaining for epithelial proliferation. Weighted gene coexpression network analysis was used to link uterine gene expression patterns and epithelial proliferation. In V-treated mice, 88 transcripts were differentially expressed (DEG) in <i>Ezh2</i>cKO mice, and <i>Bmp5, Crabp2, Lgr5</i>, and <i>Sprr2f</i> were upregulated. E2 treatment resulted in 40 DEG with <i>Krt5, Krt15, Olig3, Crabp1</i>, and <i>Serpinb7</i> upregulated in <i>Ezh2</i>cKO compared with control mice. Transcript analysis relative to proliferation rates revealed two module eigengenes correlated with epithelial proliferation in WT V vs. <i>Ezh2</i>cKO V and WT E2 vs. <i>Ezh2</i>cKO E2 mice, with a positive relationship in the former and inverse in the latter. Notably, the ESR1, Wnt, and Hippo signaling pathways were among those functionally enriched in <i>Ezh2</i>cKO females. Current results reveal unique gene expression patterns in <i>Ezh2</i>cKO uterus and provide insight into how loss of this critical epigenetic regulator assumingly contributes to uterine abnormalities.