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Project description:Abstract. Very little is known regarding how hormonal exposures impact the epigenetic landscape of developing tissues in the context of a whole organism, in contrast to the impact on cultured cells. Here we took a global approach to understanding how neonatal exposure to the xenoestrogen, diethylstilbestrol (DES), alters the uterine epigenome. RNA-seq and ChIP-seq (H3K4me3, H3K27me3, H3K27ac and H3K4me1) were performed on DES-treated and control uteri. The most striking finding was differential association of H3K27ac and H3K4me1 at typical and super-enhancer regions of 79% of altered genes. These peaks overlapped with previously reported estrogen receptor a (ERα) ChIP-seq peaks. Conditional uterine deletion of ERα (Esr1cKO) conferred protection of 88% of altered genes. H3K27ac ChIP-seq on Esr1cKO samples showed that 72% of protected genes had a differential H3K27ac enhancer. These data suggest that DES regulates gene expression in the neonatal mouse uterus by H3K27ac association at ERα binding sites near estrogen-regulated genes.
2018-03-27 | GSE104401 | GEO
Project description:Abstract. Very little is known regarding how hormonal exposures impact the epigenetic landscape of developing tissues in the context of a whole organism, in contrast to the impact on cultured cells. Here we took a global approach to understanding how neonatal exposure to the xenoestrogen, diethylstilbestrol (DES), alters the uterine epigenome. RNA-seq and ChIP-seq (H3K4me3, H3K27me3, H3K27ac and H3K4me1) were performed on DES-treated and control uteri. The most striking finding was differential association of H3K27ac and H3K4me1 at typical and super-enhancer regions of 79% of altered genes. These peaks overlapped with previously reported estrogen receptor a (ERα) ChIP-seq peaks. Conditional uterine deletion of ERα (Esr1cKO) conferred protection of 88% of altered genes. H3K27ac ChIP-seq on Esr1cKO samples showed that 72% of protected genes had a differential H3K27ac enhancer. These data suggest that DES regulates gene expression in the neonatal mouse uterus by H3K27ac association at ERα binding sites near estrogen-regulated genes.
2018-03-27 | GSE104400 | GEO
Project description:ERα Dependent Alterations in the Epigenetic Landscape of the Mouse Uterus Following Neonatal Estrogen Exposure
| PRJNA412536 | ENA
Project description:ERα Dependent Alterations in the Epigenetic Landscape of the Mouse Uterus Following Neonatal Estrogen Exposure [RNA-Seq]
| PRJNA412538 | ENA
Project description:ERα Dependent Alterations in the Epigenetic Landscape of the Mouse Uterus Following Neonatal Estrogen Exposure [ChIP-Seq]
| PRJNA412539 | ENA
Project description:Neonatal exposure to diethylstilbestrol (DES) causes permanent alterations in female reproductive tract gene expression, infertility, and uterine cancer in mice. To determine whether epigenetic mechanisms could explain these phenotypes, we first tested whether DES altered uterine expression of chromatin-modifying proteins. DES treatment significantly reduced expression of methylcytosine dioxygenase TET oncogene family, member 1 (TET1) on postnatal day 5; this decrease was correlated with a subtle decrease in DNA 5-hydroxymethylcytosine in adults. There were also significant reductions in histone methyltransferase enhancer of zeste homolog 2 (EZH2), histone lysine acetyltransferase 2A (KAT2A), and histone deacetylases HDAC1, HDAC2, and HDAC3. Uterine chromatin immunoprecipitation was used to analyze the locus-specific association of modified histones with 2 genes, lactoferrin (Ltf) and sine oculis homeobox 1 (Six1), which are permanently upregulated in adults after neonatal DES treatment. Three histone modifications associated with active transcription, histone H3 lysine 9 acetylation (H3K9ac), H3 lysine 4 trimethylation (H3K4me3), and H4 lysine 5 acetylation (H4K5ac) were enriched at specific Ltf promoter regions after DES treatment, but this enrichment was not maintained in adults. H3K9ac, H4K5ac, and H3K4me3 were enriched at Six1 exon 1 immediately after neonatal DES treatment. As adults, DES-treated mice had greater differences in H4K5ac and H3K4me3 occupancy at Six1 exon 1 and new differences in these histone marks at an upstream region. These findings indicate that neonatal DES exposure temporarily alters expression of multiple chromatin-modifying proteins and persistently alters epigenetic marks in the adult uterus at the Six1 locus, suggesting a mechanism for developmental exposures leading to altered reproductive function and increased cancer risk.
| S-EPMC3787132 | biostudies-literature
Project description:The Estrogen Receptor alpha (ERα) controls key cellular functions in hormone responsive breast cancer by assembling in large functional multiprotein complexes. ERα ligands are classified as agonists and antagonist, according to the response they elicit, thus the molecular characterization of the of ERα nuclear iteractome composition following estrogen and antiestrogen stimulation whose is needed to understand their effects on estrogen target tissues, in particular breast cancer. To this aim interaction proteomics coupled to mass spectrometry (MS) was applied to map the ERα nuclear interacting partners in MCF7 breast cancer cell nuclei following estrogen and antiestrogen stimuli.
2020-09-02 | PXD018709 | Pride
Project description:Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (KISS1)-neuron pulsatility in the arcuate hypothalamic nucleus, while also exerting a surge-like effect on KISS1-neuron activity in the AVPV hypothalamic nucleus. However, a mechanistic basis for this region-specific effect has remained elusive. Our genomic analysis in female mice demonstrate that some processes, such as restraint of KISS1-neuron activity in the arcuate nucleus, may be explained by region-specific estrogen receptor alpha (ERα) DNA binding at gene regulatory regions. Furthermore, we find that the Kiss1-locus is uniquely regulated in these hypothalamic nuclei, and that the nuclear receptor co-repressor NR0B1 (DAX1) restrains its transcription specifically in the arcuate nucleus. These studies provide mechanistic insight into how ERα may control the KISS1-neuron, and Kiss1 gene expression, to couple gonadotropin release to the developmental stage of the oocyte.
| S-EPMC10227040 | biostudies-literature
Project description:BackgroundFemale reproductive tract development is sensitive to the endocrine-disrupting potential of environmental estrogens. Early-life exposure to the dietary phytoestrogen genistein impairs fertility and persistently alters the transcriptome in the oviduct and uterus of rodents. Glucocorticoid signaling, which has recently been shown to be essential for normal fertility in the female mouse uterus, is antagonized by genistein.ObjectiveOur goal was to determine whether early-life exposure to genistein disrupts glucocorticoid signaling in the mouse uterus, which may contribute to infertility.MethodsFemale C57Bl/6 mice were exposed to either 50 mg/kg per day genistein, 10 μg/kg per day estradiol, or vehicle (corn oil) on postnatal days 1-5 (PND1-5), and then treated with the synthetic glucocorticoid dexamethasone (Dex: 1 mg/kg) or vehicle (saline) on PND5, at weaning on PND21, or as adults on PND56 following adrenalectomy and ovariectomy to evaluate glucocorticoid responsiveness. Uteri were isolated following treatment for gene expression or chromatin immunoprecipitation.ResultsNeonatal exposure to genistein altered the uterine transcriptome of adult mice and caused substantial changes to the transcriptional response to glucocorticoids. Although expression of the glucocorticoid receptor was not affected, genistein exposure disrupted glucocorticoid receptor recruitment to specific regulatory sites in target genes. Many genes involved in chromatin remodeling were dysregulated in genistein-exposed mice, suggesting that epigenetic reprograming may contribute to the altered glucocorticoid response of the uterus following early-life exposure to genistein. These changes affected the biological activity of glucocorticoids within the uterus, as glucocorticoids antagonized the proliferative effects of estradiol in the uterus of control mice but not genistein-exposed mice.ConclusionsOur findings suggest that disruption of glucocorticoid signaling due to early-life exposure to environmental estrogens may in part render the uterus unable to support implantation. https://doi.org/10.1289/EHP1575.
| S-EPMC6071733 | biostudies-literature
Project description:Exposure to endocrine-disrupting chemicals during development could alter the epigenetic programming of the genome and result in adult-onset disease. Methoxychlor (MXC) and its metabolites possess estrogenic, antiestrogenic, and antiandrogenic activities. Previous studies showed that fetal/neonatal exposure to MXC caused adult ovarian dysfunction due to altered expression of key ovarian genes including estrogen receptor (ER)-beta, which was down-regulated, whereas ERalpha was unaffected. The objective of the current study was to evaluate changes in global and gene-specific methylation patterns in adult ovaries associated with the observed defects. Rats were exposed to MXC (20 microg/kgxd or 100 mg/kg.d) between embryonic d 19 and postnatal d 7. We performed DNA methylation analysis of the known promoters of ERalpha and ERbeta genes in postnatal d 50-60 ovaries using bisulfite sequencing and methylation-specific PCRs. Developmental exposure to MXC led to significant hypermethylation in the ERbeta promoter regions (P < 0.05), whereas the ERalpha promoter was unaffected. We assessed global DNA methylation changes using methylation-sensitive arbitrarily primed PCR and identified 10 genes that were hypermethylated in ovaries from exposed rats. To determine whether the MXC-induced methylation changes were associated with increased DNA methyltransferase (DNMT) levels, we measured the expression levels of Dnmt3a, Dnmt3b, and Dnmt3l using semiquantitative RT-PCR. Whereas Dnmt3a and Dnmt3l were unchanged, Dnmt3b expression was stimulated in ovaries of the 100 mg/kg MXC group (P < 0.05), suggesting that increased DNMT3B may cause DNA hypermethylation in the ovary. Overall, these data suggest that transient exposure to MXC during fetal and neonatal development affects adult ovarian function via altered methylation patterns.
| S-EPMC2754680 | biostudies-literature