Mice lacking uterine enhancer of zeste homolog 2 have transcriptomic changes associated with uterine epithelial proliferation
| Autor: | Duolin Wang, Manjunatha K. Nanjappa, Jiude Mao, Paul S. Cooke, Theresa I. Medrano, Jessica A. Kinkade, Yang Liu, Zhen Lyu, Trupti Joshi, Cheryl S. Rosenfeld, Sergei G. Tevosian, Fahong Yu, Ana M Mesa |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Heterozygote Genotype Physiology Uterus RNA-Seq Biology Endometrium Epigenesis Genetic Transcriptome Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Gene expression Genetics medicine Animals Cluster Analysis Enhancer of Zeste Homolog 2 Protein Epigenetics Cell Proliferation Mice Knockout Estradiol Gene Expression Profiling EZH2 Computational Biology Estrogens Up-Regulation Cell biology Wnt Proteins 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation 030220 oncology & carcinogenesis Histone methyltransferase Female Signal Transduction Research Article |
| Zdroj: | Physiol Genomics |
| ISSN: | 1531-2267 1094-8341 |
| DOI: | 10.1152/physiolgenomics.00098.2019 |
| Popis: | 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 ( Ezh2cKO) uteri to obtain mechanistic insights into the gene expression changes that underpin the pathogenesis observed in these mice. Ovariectomized adult Ezh2cKO 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 Ezh2cKO mice, and Bmp5, Crabp2, Lgr5, and Sprr2f were upregulated. E2 treatment resulted in 40 DEG with Krt5, Krt15, Olig3, Crabp1, and Serpinb7 upregulated in Ezh2cKO compared with control mice. Transcript analysis relative to proliferation rates revealed two module eigengenes correlated with epithelial proliferation in WT V vs. Ezh2cKO V and WT E2 vs. Ezh2cKO 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 Ezh2cKO females. Current results reveal unique gene expression patterns in Ezh2cKO uterus and provide insight into how loss of this critical epigenetic regulator assumingly contributes to uterine abnormalities. |
| Databáze: | OpenAIRE |
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