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

• Published in: Physiological genomics 2020-02, Vol.52 (2), p.81-95
• Main Authors: Mesa, Ana M, Mao, Jiude, Nanjappa, Manjunatha K, Medrano, Theresa I, Tevosian, Sergei, Yu, Fahong, Kinkade, Jessica, Lyu, Zhen, Liu, Yang, Joshi, Trupti, Wang, Duolin, Rosenfeld, Cheryl S, Cooke, Paul S
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Animals; Cell Proliferation; Clonal deletion; Cluster Analysis; Computational Biology; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic; Epithelial cells; ESR1 protein; Estradiol - pharmacology; Estrogens - metabolism; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Genotype; Heterozygote; Histone methyltransferase; Mice; Mice, Knockout; Ovariectomy; Phosphatidylinositol 3-Kinases - metabolism; Ribonucleic acid; RNA; RNA-Seq; Signal Transduction; Transcription; Transcriptome; Up-Regulation; Uterus; Uterus - abnormalities; Uterus - metabolism; Wnt protein; Wnt Proteins - metabolism
• ISSN: 1094-8341; 1531-2267
• DOI: 10.1152/physiolgenomics.00098.2019

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 ( cKO) uteri to obtain mechanistic insights into the gene expression changes that underpin the pathogenesis observed in these mice. Ovariectomized adult 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 cKO mice, and , and were upregulated. E2 treatment resulted in 40 DEG with , and upregulated in cKO compared with control mice. Transcript analysis relative to proliferation rates revealed two module eigengenes correlated with epithelial proliferation in WT V vs. cKO V and WT E2 vs. 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 cKO females. Current results reveal unique gene expression patterns in cKO uterus and provide insight into how loss of this critical epigenetic regulator assumingly contributes to uterine abnormalities.