Steroid Hormones Regulate Genome-Wide Epigenetic Programming and Gene Transcription in Human Endometrial Cells with Marked Aberrancies in Endometriosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE145702 | GEO | 2020/02/21
REPOSITORIES: GEO
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Project description:Programmed cellular responses to cycling ovarian-derived steroid hormones are central to normal endometrial function. Abnormalities therein, as in the estrogen-dependent, progesterone-"resistant" disorder, endometriosis, predispose to infertility and poor pregnancy outcomes. The endometrial stromal fibroblast (eSF) is a master regulator of pregnancy success. However, the complex hormone-epigenome-transcriptome interplay in eSF by each individual steroid hormone, estradiol (E2) and/or progesterone (P4), under physiologic and pathophysiologic conditions, is poorly understood and was investigated herein. Genome-wide analysis in normal, early and late stage eutopic eSF revealed: i) In contrast to P4, E2 extensively affected the eSF DNA methylome and transcriptome. Importantly, E2 resulted in a more open versus closed chromatin, confirmed by histone modification analysis. Combined E2 with P4 affected a totally different landscape than E2 or P4 alone. ii) P4 responses were aberrant in early and late stage endometriosis, and mapping differentially methylated CpG sites with progesterone receptor targets from the literature revealed different but not decreased P4-targets, leading to question the P4-"resistant" phenotype in endometriosis. Interestingly, an aberrant E2-response was noted in eSF from endometriosis women; iii) Steroid hormones affected specific genomic contexts and locations, significantly enriching enhancers and intergenic regions and minimally involving proximal promoters and CpG islands, regardless of hormone type and eSF disease state. iv) In eSF from women with endometriosis, aberrant hormone-induced methylation signatures were mainly due to existing DNA methylation marks prior to hormone treatments and involved known endometriosis genes and pathways. v) Distinct DNA methylation and transcriptomic signatures revealed early and late stage endometriosis comprise unique disease subtypes. Taken together, the data herein, for the first time, provide significant insight into the hormone-epigenome-transcriptome interplay of each steroid hormone in normal eSF, and aberrant E2 response, distinct disease subtypes, and pre-existing epigenetic aberrancies in the setting of endometriosis, provide mechanistic insights into how endometriosis affects endometrial function/dysfunction.
| S-EPMC7299312 | biostudies-literature
Project description:Genome-wide DNA methylation profiling of hormone treated normal and endometriosis stromal fibroblast cells (eSF). The Illumina Infinium Methylation BeadChip array 450 (HM450) was used. Samples include 4 normal of no uterine pathology (NUP), 4 endometriosis stage I, 4 endometriosis stage IV samples, each treated with Estrogen (E2), Progesterone (P4), E2+P4, or vehicle (veh), for a total of 48 samples analyzed on HM450.
2020-02-22 | GSE130028 | GEO
Project description:Gene expression profiling of hormone treated normal and endometriosis stromal fibroblast cells (eSF). We used Affymetrix Human Gene 1.0 ST arrays. Samples include 4 normal of no uterine pathology (NUP), 4 endometriosis stage I, 4 endometriosis stage IV samples, each treated with Estrogen (E2), Progesterone (P4), E2+P4, or vehicle (veh), for a total of 48 samples on the Affymetrix platform.
2020-02-21 | GSE145701 | GEO
Project description:Steroid Hormones Regulate Genome-Wide Epigenetic Programming and Gene Transcription in Human Endometrial Cells with Marked Aberrancies in Endometriosis
| PRJNA607970 | ENA
Project description:Steroid Hormones Regulate Genome-Wide Epigenetic Programming and Gene Transcription in Human Endometrial Cells with Marked Aberrancies in Endometriosis [methylation]
| PRJNA533613 | ENA
Project description:Steroid Hormones Regulate Genome-Wide Epigenetic Programming and Gene Transcription in Human Endometrial Cells with Marked Aberrancies in Endometriosis [expression]
| PRJNA607977 | ENA
Project description:BACKGROUND:Evidence suggests that eutopic endometrium from women with endometriosis (US-E) has intrinsic functional anomalies compared with women without endometriosis (US-C). We hypothesized that differences in endometrial haptoglobin (eHp) mRNA and protein levels exist between eutopic endometrium from US-E and US-C and that inflammatory mediators may be involved. METHODS:Endometrial stromal cells and tissue explants from US-E (n = 18) and US-C (n = 18) were cultured (24 h/48 h for cells/explants) with interleukin (IL)-1alpha, -1beta, -6, -8 or tumor necrosis factor-alpha (TNF-alpha) at 0-100 ng/ml. eHp protein in media and mRNA levels were quantified by enzyme-linked immunosorbent assay and quantitative PCR. RESULTS:In eutopic endometrial stromal cells from US-E, IL-1beta, IL-6 and TNF-alpha (10 ng/ml) increased eHp mRNA levels (P = 0.002, P < 0.001 and P < 0.001, respectively) and eHp protein (P = 0.023, 0.031 and 0.006, respectively) versus control. In endometrial tissues from US-E, IL-1beta, IL-6 and TNF-alpha increased eHp mRNA (P < 0.001, P = 0.017 and P < 0.001, respectively) and eHp protein (P < 0.001, P = 0.007 and 0.039, respectively) versus control. IL-1alpha and IL-8 had small or no effects on isolated endometrial cells or tissues. In US-C, IL-1beta, IL-8 and TNF-alpha each reduced eHp mRNA in endometrial stromal cells (all P < 0.001) versus control; IL-1alpha and IL-6 had no effect. eHp mRNA increased in endometrial tissues from US-C in response to IL-1beta (P = 0.008), IL-6 (P = 0.015) and TNF-alpha (P = 0.031) versus control; IL-1alpha or IL-8 had no effect. CONCLUSIONS:Endometrium from US-E differentially responds to specific inflammatory cytokines by production of eHp. We propose that up-regulation of endometrial eHp by inflammatory mediators disrupts normal endometrial function and may facilitate the pathogenesis of endometriosis.
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Project description:Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor's transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback mechanism to regulate P4-responsive genes. Conversely, in endometrial pathology (endometriosis), E2-induced GREB1 modulates E2-dependent gene expression to promote the growth of endometriotic lesions in mice. This differential action of GREB1 exerted by a common feed-forward mechanism with steroid receptors advances our understanding of mechanisms that underlie cell- and tissue-specific steroid hormone actions.
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Project description:Leptin is an adipokine produced by fat cells that regulates food consumption and metabolic activity. Sexual dimorphism in leptin and fat stores have been observed in humans and rodents with females having more leptin and greater levels of subcutaneous fat than males. One potential mechanism leading to this dimorphism is steroid hormone regulated synthesis of transcripts encoding leptin. Identification of direct regulatory mechanisms is difficult in animals or primary adipocytes due to these intertwined dimorphisms. We used well-characterized 3T3-L1 murine adipocytes to demonstrate that dihydrotestosterone (DHT) reduced Leptin (Lep) transcript abundance and cytosolic and secreted leptin protein. The magnitude of this effect was greatest on secreted leptin, which was decreased by DHT to 30% of the control. In contrast, 17β-estradiol significantly increased the abundance of transcripts encoding leptin and increased secreted leptin to 230% of the control. Treatment with estrogen and androgen receptor antagonists had opposite effects on Lep transcript abundance to steroid treatments, indicating that these transcriptional effects are mediated through the canonical steroid hormone signaling pathways. These results indicate that short-term treatments with steroid hormones are sufficient to alter both Lep transcript accumulation and leptin protein secretion, and may play a role in the sexual dimorphism of this adipokine.
| S-EPMC5558017 | biostudies-literature
Project description:Endometrium is the uterine lining that undergoes hundreds of cycles of proliferation, differentiation, and desquamation throughout a woman's reproductive life. Recently, much attention is paid to the appropriate endometrial functioning, as decreased endometrial receptivity is stated to be one of the concerns heavily influencing successes of embryo implantation rates and the efficacy of in vitro fertilization (IVF) treatment. In order to acquire and maintain the desired endometrial receptivity during IVF cycles, luteal phase support by various progestagens or other hormonal combinations is generally recommended. However, today, the selection of the specific hormonal therapy during IVF seems to be empirical, mainly due to a lack of appropriate tools for personalized approach. Here, we designed the genetic tool for patient-specific optimization of hormonal supplementation schemes required for the maintenance of endometrial receptivity during luteal phase. We optimized and characterized in vitro endometrial stromal cell (ESC) decidualization model as the adequate physiological reflection of endometrial sensitivity to steroid hormones. Based on the whole transcriptome RNA sequencing and the corresponding bioinformatics, we proposed that activation of the decidual prolactin (PRL) promoter containing ancient transposons MER20 and MER39 may reflect functioning of the core decidual regulatory network. Furthermore, we cloned the sequence of decidual PRL promoter containing MER20 and part of MER39 into the expression vector to estimate the effectiveness of ESC decidual response and verified sensitivity of the designed system. We additionally confirmed specificity of the generated tool using human diploid fibroblasts and adipose-derived human mesenchymal stem cells. Finally, we demonstrated the possibility to apply our tool for personalized hormone screening by comparing the effects of natural progesterone and three synthetic analogs (medroxyprogesterone 17-acetate, 17α-hydroxyprogesterone caproate, dydrogesterone) on decidualization of six ESC lines obtained from patients planning to undergo the IVF procedure. To sum up, we developed the "all-in-one" genetic tool based on the MER20/MER39 expression cassette that provides the ability to predict the most appropriate hormonal cocktail for endometrial receptivity maintenance specifically and safely for the patient, and thus to define the personal treatment strategy prior to the IVF procedure.
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