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Adiposity alters protective mechanisms of progesterone through dysregulation of endometrial metallothionein expression

ABSTRACT: In this study, we sought to understand the effects of excess adipose on the benign endometrium. We used a physiologic in vitro coculture system consisting of multicellular organoids of the benign human endometrium and adipose spheroids in the presence of estradiol, progesterone, and testosterone to mimic the menstrual cycle. Gene expression analysis of endometrial organoids under high adiposity conditions revealed downregulation of genes normally expressed in secretory endometrium, suggestive of an altered progesterone response. Genes associated with ion homeostasis and detoxification of reactive oxygen species were also downregulated, including the metallothionein (MT) family of genes. We demonstrated that MT gene expression in endometrial organoids was regulated by progesterone specifically in the epithelial cells, and that progesterone receptor is recruited to the promoters of MT genes in endometrial epithelial cells. We illustrated the impact of MT dysregulation by silencing MT genes in endometrial epithelial cells, resulting in increased DNA damage. Our results reveal that exposing the endometrium to high adiposity can compromise the protective effects of progesterone, dysregulate MT genes in the endometrial epithelium, and leave the endometrium vulnerable to ROS-induced DNA damage.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240926 | GEO | 2024/04/19

REPOSITORIES: GEO

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Differential expression of Wnt signalling molecules between pre- and post-menopausal endometrial epithelial cells suggests that a population of putative epithelial stem/progenitor cells reside in the basalis layer

Project description:The human endometrium is a highly regenerative tissue that undergoes cyclical proliferation, differentiation and shedding each month. The upper functionalis layer of the endometrium is shed in response to circulating levels of estrogen and progesterone, while the lower basalis layer remains. Clonogenic epithelial stem/progenitor cells likely responsible for regenerating endometrial epithelium have been identified in pre-menopausal (Pre-M) and post-menopausal (Post-M) endometrium and may reside in the basalis layer. We undertook a transcriptional profiling of purified epithelial cells from full-thickness Pre-M and Post-M endometrium to identify differentially expressed genes. The hypothesis tested in the present study was that Post-M endometrial epithelial gene profile would be similar to the quiescent basalis epithelium of Pre-M endometrium. We found striking differential gene expression of many Wnt family members between Pre-M and Post-M and other stem cell network genes. Comparative analysis of our endometrial epithelial gene expression profiles to that of endometrial epithelial cells in remodelling endometrium also provides new evidence showing that Post-M endometrial epithelium has a similar gene signature to that of basalis epithelium of menstrual endometrium. Human endometrial tissue was obtained from 8 pre-menopausal and 3 post-menopausal women undergoing hysterectomy for various benign gynaecologic conditions. Endometrial tissue was digested and isolated using combination of DNase and collagenase. Anti-human EpCAM antibody-coated magnetic Dynabeads was used to positively select total epithelial cells from the digested single cell suspensions. Total RNA was extracted from the purified endometrial epithelial cells and hybridised to Illumina Sentrix HT12 beadchip. Resulting data was compared between pre-menopausal and post-menopausal samples.

2012-04-10 | E-GEOD-35221 | biostudies-arrayexpress

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2012-04-11 | GSE35221 | GEO

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Project description:Progesterone signaling in endometrial epithelial organoids

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2023-05-10 | PXD036535 | Pride

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2013-08-23 | E-GEOD-47577 | biostudies-arrayexpress

Comparison of organoids from Menstrual Fluid and Hormone-treated Endometrium: Novel tools for Gynaecological Research

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2021-05-05 | E-MTAB-10375 | biostudies-arrayexpress

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