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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE157503 | GEO | 2023/08/07

REPOSITORIES: GEO

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Developmental reprogramming of myometrial stem cells by endocrine disruptor linking to risk of uterine fibroids.

Project description:BackgroundThe stage, when tissues and organs are growing, is very vulnerable to environmental influences, but it's not clear how exposure during this time causes changes to the epigenome and increases the risk of hormone-related illnesses like uterine fibroids (UFs).MethodsDevelopmental reprogramming of myometrial stem cells (MMSCs), the putative origin from which UFs originate, was investigated in vitro and in the Eker rat model by RNA-seq, ChIP-seq, RRBS, gain/loss of function analysis, and luciferase activity assays.ResultsWhen exposed to the endocrine-disrupting chemical (EDC) diethylstilbestrol during Eker rat development, MMSCs undergo a reprogramming of their estrogen-responsive transcriptome. The reprogrammed genes in MMSCs are known as estrogen-responsive genes (ERGs) and are activated by mixed lineage leukemia protein-1 (MLL1) and DNA hypo-methylation mechanisms. Additionally, we observed a notable elevation in the expression of ERGs in MMSCs from Eker rats exposed to natural steroids after developmental exposure to EDC, thereby augmenting estrogen activity.ConclusionOur studies identify epigenetic mechanisms of MLL1/DNA hypo-methylation-mediated MMSC reprogramming. EDC exposure epigenetically targets MMSCs and leads to persistent changes in the expression of a subset of ERGs, imparting a hormonal imprint on the ERGs, resulting in a "hyper-estrogenic" phenotype, and increasing the hormone-dependent risk of UFs.

| S-EPMC10471700 | biostudies-literature

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

Project description: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.

2023-08-07 | GSE157502 | GEO

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

2023-08-07 | GSE157500 | GEO

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

Project description: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.

2023-08-07 | GSE157498 | GEO

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

Project description:Developmental Reprogramming of Myometrial Stem Cells by Endocrine Disruptor Linking to Risk of Uterine Fibroids

| PRJNA661524 | ENA

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

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

| PRJNA661531 | ENA

Endocrine disruptor exposure during development increases incidence of uterine fibroids by altering DNA repair in myometrial stem cells.

Project description:Despite the major negative impact uterine fibroids (UFs) have on female reproductive health, little is known about early events that initiate development of these tumors. Somatic fibroid-causing mutations in mediator complex subunit 12 (MED12), the most frequent genetic alterations in UFs (up to 85% of tumors), are implicated in transforming normal myometrial stem cells (MSCs) into tumor-forming cells, though the underlying mechanism(s) leading to these mutations remains unknown. It is well accepted that defective DNA repair increases the risk of acquiring tumor-driving mutations, though defects in DNA repair have not been explored in UF tumorigenesis. In the Eker rat UF model, a germline mutation in the Tsc2 tumor suppressor gene predisposes to UFs, which arise due to "second hits" in the normal allele of this gene. Risk for developing these tumors is significantly increased by early-life exposure to endocrine-disrupting chemicals (EDCs), suggesting increased UF penetrance is modulated by early drivers for these tumors. We analyzed DNA repair capacity using analyses of related gene and protein expression and DNA repair function in MSCs from adult rats exposed during uterine development to the model EDC diethylstilbestrol. Adult MSCs isolated from developmentally exposed rats demonstrated decreased DNA end-joining ability, higher levels of DNA damage, and impaired ability to repair DNA double-strand breaks relative to MSCs from age-matched, vehicle-exposed rats. These data suggest that early-life developmental EDC exposure alters these MSCs' ability to repair and reverse DNA damage, providing a driver for acquisition of mutations that may promote the development of these tumors in adult life.

| S-EPMC6203880 | biostudies-other

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

Project description:Developmental Reprogramming of Myometrial Stem Cells by Endocrine Disruptor Linking to Risk of Uterine Fibroids [ChIP-Seq]

| PRJNA661491 | ENA

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

Project description:Developmental Reprogramming of Myometrial Stem Cells by Endocrine Disruptor Linking to Risk of Uterine Fibroids [RNA-Seq]

| PRJNA661527 | ENA

Epigenetic Modulation of Inflammatory Pathways in Myometrial Stem Cells and Risk of Uterine Fibroids.

Project description:The period during which tissue and organ development occurs is particularly vulnerable to the influence of environmental exposures. However, the specific mechanisms through which biological pathways are disrupted in response to developmental insults, consequently elevating the risk of hormone-dependent diseases, such as uterine fibroids (UFs), remain poorly understood. Here, we show that developmental exposure to the endocrine-disrupting chemical (EDC), diethylstilbestrol (DES), activates the inflammatory pathways in myometrial stem cells (MMSCs), which are the origin of UFs. Significantly, the secretome of reprogrammed MMSCs enhances the expression of critical inflammation-related genes in differentiated myometrial cells through the paracrine mechanism, which amplifies pro-inflammatory and immune suppression signaling in the myometrium. The expression of reprogrammed inflammatory responsive genes (IRGs) is driven by activated mixed-lineage leukemia protein-1 (MLL1) in MMSCs. The deactivation of MLL reverses the reprogramming of IRG expression. In addition, the inhibition of histone deacetylases (HDACs) also reversed the reprogrammed IRG expression induced by EDC exposure. This work identifies the epigenetic mechanisms of MLL1/HDAC-mediated MMSC reprogramming, and EDC exposure epigenetically targets MMSCs and imparts an IRG expression pattern, which may result in a "hyper-inflammatory phenotype" and an increased hormone-dependent risk of UFs later in life.

| S-EPMC10380326 | biostudies-literature

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