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Developmental Reprogramming of Myometrial Stem Cells by Endocrine Disruptor Linking to Risk of Uterine Fibroids [RRBS]

ABSTRACT: We report that developmental exposure to the endocrine disrupting chemical (EDC) diethylstilbestrol increases the estrogen action in myometrial stem cells (MMSCs), the origin from which UFs originate. The expression of reprogrammed estrogen responsive genes (ERGs) is driven by activated mixed lineage leukemia protein-1 (MLL1) in MMSCs. Deactivation of MLL1 reverses reprogramming of ERG expression. In addition, upregulation of ERGs occurs via DNA hypomethylation mechanism. Furthermore, the secretome of reprogrammed MMSCs enhances the proliferation of differentiated myometrial cells through activation of β-catenin signaling. This work identifies epigenetic mechanisms of MLL1/DNA methyltransferase- mediated MMSC reprogramming, and EDC exposure epigenetically targets MMSCs and imparts a hormonal imprint on the ERGs resulting in a “hyper-estrogenized” phenotype and increased hormone-dependent risk of UFs.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE157502 | GEO | 2023/08/07

REPOSITORIES: GEO

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Project description:Endocrine disrupting chemicals (EDCs) such as bisphenol S (BPS) are xenobiotic compounds that can disrupt endocrine signaling following exposure due to steric similarities to endogenous hormones within the body. EDCs have been shown to induce disruptions in normal epigenetic programming (epimutations) that accompany dysregulation of normal gene expression patterns that appear to predispose disease states. Most interestingly, the prevalence of epimutations following exposure to many different EDCs often persists over multiple subsequent generations, even with no further exposure to the causative EDC. Many previous studies have described both the direct and prolonged effects of EDC exposure in animal models, but many questions remain about molecular mechanisms by which EDCs initially induce epimutations or contribute to the propagation of EDC-induced epimutations either within the exposed generation or to subsequent generations. Additional questions remain regarding the extent to which there may be differences in cell type-specific susceptibilities to various EDCs, and whether this susceptibility is correlative with expression of relevant hormone receptors and/or the location of relevant hormone response elements (HREs) in the genome. To address these questions, we exposed cultured mouse pluripotent (induced pluripotent stem [iPS]), somatic (Sertoli and granulosa), and germ (primordial germ cell like [PGCLCs]) cells to BPS and measured changes in DNA methylation levels at the epigenomic level and gene expression at the transcriptomic level. We found that there was indeed a difference in cell type-specific susceptibility to EDC-induced epimutagenesis and that this susceptibility correlated with differential expression of relevant hormone receptors and, in many cases, tended to generate epimutations near relevant HREs within the genome. Additionally, however, we also found that BPS can induce epimutations in a cell type that does not express relevant receptors and in genomic regions that do not contain relevant HREs, suggesting that both canonical and non-canonical signaling mechanisms can be disrupted by BPS exposure. Most interestingly, we found that when iPS cells were exposed to BPS and then induced to differentiate into PGCLCs, the prevalence of epimutations and differentially expressed genes (DEGs) initially induced in the iPSCs was largely retained in the resulting PGCLCs, however, >90% of the specific epimutations and DEGs were not conserved but were rather replaced by novel epimutations and DEGs following the iPSC to PGCLC transition. These results suggest a unique mechanism by which an EDC-induced epimutated state may be propagated transgenerationally following a single exposure to the causative EDC.

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Developmental Reprogramming of Myometrial Stem Cells by Endocrine Disruptor Linking to Risk of Uterine Fibroids [RRBS]

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