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3 August 2021 Spatial transcriptomics analysis of uterine gene expression in enhancer of zeste homolog 2 conditional knockout mice
Ana M. Mesa, Jiude Mao, Theresa I. Medrano, Nathan J. Bivens, Alexander Jurkevich, Geetu Tuteja, Paul S. Cooke, Cheryl S. Rosenfeld
Author Affiliations +
Abstract

Histone proteins undergo various modifications that alter chromatin structure, including addition of methyl groups. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that methylates lysine residue 27, and thereby suppresses gene expression. EZH2 plays integral roles in the uterus and other reproductive organs. We have previously shown that conditional deletion of uterine EZH2 results in increased proliferation of luminal and glandular epithelial cells, and RNA-seq analyses reveal several uterine transcriptomic changes in Ezh2 conditional (c) knockout (KO) mice that can affect estrogen signaling pathways. To pinpoint the origin of such gene expression changes, we used the recently developed spatial transcriptomics (ST) method with the hypotheses that Ezh2cKO mice would predominantly demonstrate changes in epithelial cells and/or ablation of this gene would disrupt normal epithelial/stromal gene expression patterns. Uteri were collected from ovariectomized adult WT and Ezh2cKO mice and analyzed by ST. Asb4, Cxcl14, Dio2, and Igfbp5 were increased, Sult1d1, Mt3, and Lcn2 were reduced in Ezh2cKO uterine epithelium vs. WT epithelium. For Ezh2cKO uterine stroma, differentially expressed key hub genes included Cald1, Fbln1, Myh11, Acta2, and Tagln. Conditional loss of uterine Ezh2 also appears to shift the balance of gene expression profiles in epithelial vs. stromal tissue toward uterine epithelial cell and gland development and proliferation, consistent with uterine gland hyperplasia in these mice. Current findings provide further insight into how EZH2 may selectively affect uterine epithelial and stromal compartments. Additionally, these transcriptome data might provide mechanistic understanding and valuable biomarkers for human endometrial disorders with epigenetic underpinnings.

Summary sentence

Spatial transcriptomics studies reveal how EZH2 selectively affects uterine epithelial and stromal compartments, and findings may provide a mechanistic understanding and biomarkers for human endometrial disorders originating from epigenetic changes.

Graphical Abstract

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© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Ana M. Mesa, Jiude Mao, Theresa I. Medrano, Nathan J. Bivens, Alexander Jurkevich, Geetu Tuteja, Paul S. Cooke, and Cheryl S. Rosenfeld "Spatial transcriptomics analysis of uterine gene expression in enhancer of zeste homolog 2 conditional knockout mice," Biology of Reproduction 105(5), 1126-1139, (3 August 2021). https://doi.org/10.1093/biolre/ioab147
Received: 25 May 2021; Accepted: 22 July 2021; Published: 3 August 2021
KEYWORDS
endometrial cancer
Endometrium
epigenetics
estrogen
female reproduction
histone proteins
RNA-seq
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