A SRC-3 gene signature in predecidual T-HESC
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE210936 | GEO | 2022/11/15
REPOSITORIES: GEO
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Project description:Ovarian estrogen (E2) and progesterone (P4) are indispensable for embryo-implantation and endometrial stromal decidualization; however, the molecular mechanisms that underpin these reproductive processes are unclear. Steroid receptor coregulator-2 (SRC-2) belongs to the multifunctional SRC/p160 family which also includes SRC-1 and SRC-3. Sharing strong sequence homology, all three SRCs exert diverse regulatory effects by modulating the transcriptional potency of nuclear receptor family members, including the estrogen and progesterone receptor (ER and PR respectively). Importantly, absence of SRC-2 in PR positive cells in the epithelial, stromal, and myometrial compartments of the murine uterus results in a striking infertility defect. This reproductive phenotype highlights a key role for SRC-2 in uterine function which is not shared with other coregulators. Intriguingly, abrogation of uterine SRC-2 does not block embryo apposition or attachment to the apical surface of luminal epithelial cells of the endometrium but rather prevents P4-dependent local decidualization of the sub-epithelial stroma. Remarkably, epithelial-specific ablation of SRC-2 in the murine uterus does not compromise endometrial functionality, again underscoring the unique importance of stromal derived SRC-2 in uterine function. The stromal decidualization defect resulting from SRC-2 ablation is reflected at the molecular level by a marked attenuation in P4 responsive target genes known to be critical for P4 dependent decidualization (i.e. ERBB receptor feedback inhibitor 1, Follistatin and Fkbp5). Conversely, the induction of E2 or P4 target genes involved in embryo implantation (i.e. leukemia inhibitory factor (LIF) and Indian hedgehog (Ihh) respectively) is not affected by SRC-2’s absence. As with mouse studies, decidualization of primary human stromal cells (HESCs) in culture is blocked by SRC-2 knockdown; however, HESC decidualization is unaffected by knockdown of SRC-1 or SRC-3. As a consequence of SRC-2 knockdown, molecular studies disclose a striking decrease in the induction of a subset of P4 target genes (i.e. WNT4 and FKBP5) which are essential for the stromal-epithelioid transformation step, the cellular hallmark of endometrial decidualization. Collectively, these studies not only showcase the evolutionary importance of SRC-2 in endometrial biology but also suggest that deregulation of this coregulator may underpin a spectrum of hormone-dependent uterine pathologies such as endometriosis and endometrial cancer. Microarray analysis was performed on mouse uteri using eighteen SRC-2flox/flox (SRC-2f/f) and eighteen PRCre/+ SRC-2flox/flox (SRC-2d/d) mice. Mice were ovariectomized at 6 weeks and after 2 weeks mice were either treated with sesame oil (vehicle) or 1 mg of P4. RNA from three mice per genotype per treatment were pooled and assigned as one sample (three samples per genotype per treatment). multiple group comparison
2014-04-01 | E-GEOD-31406 | biostudies-arrayexpress
Project description:Ovarian estrogen (E2) and progesterone (P4) are indispensable for embryo-implantation and endometrial stromal decidualization; however, the molecular mechanisms that underpin these reproductive processes are unclear. Steroid receptor coregulator-2 (SRC-2) belongs to the multifunctional SRC/p160 family which also includes SRC-1 and SRC-3. Sharing strong sequence homology, all three SRCs exert diverse regulatory effects by modulating the transcriptional potency of nuclear receptor family members, including the estrogen and progesterone receptor (ER and PR respectively). Importantly, absence of SRC-2 in PR positive cells in the epithelial, stromal, and myometrial compartments of the murine uterus results in a striking infertility defect. This reproductive phenotype highlights a key role for SRC-2 in uterine function which is not shared with other coregulators. Intriguingly, abrogation of uterine SRC-2 does not block embryo apposition or attachment to the apical surface of luminal epithelial cells of the endometrium but rather prevents P4-dependent local decidualization of the sub-epithelial stroma. Remarkably, epithelial-specific ablation of SRC-2 in the murine uterus does not compromise endometrial functionality, again underscoring the unique importance of stromal derived SRC-2 in uterine function. The stromal decidualization defect resulting from SRC-2 ablation is reflected at the molecular level by a marked attenuation in P4 responsive target genes known to be critical for P4 dependent decidualization (i.e. ERBB receptor feedback inhibitor 1, Follistatin and Fkbp5). Conversely, the induction of E2 or P4 target genes involved in embryo implantation (i.e. leukemia inhibitory factor (LIF) and Indian hedgehog (Ihh) respectively) is not affected by SRC-2’s absence. As with mouse studies, decidualization of primary human stromal cells (HESCs) in culture is blocked by SRC-2 knockdown; however, HESC decidualization is unaffected by knockdown of SRC-1 or SRC-3. As a consequence of SRC-2 knockdown, molecular studies disclose a striking decrease in the induction of a subset of P4 target genes (i.e. WNT4 and FKBP5) which are essential for the stromal-epithelioid transformation step, the cellular hallmark of endometrial decidualization. Collectively, these studies not only showcase the evolutionary importance of SRC-2 in endometrial biology but also suggest that deregulation of this coregulator may underpin a spectrum of hormone-dependent uterine pathologies such as endometriosis and endometrial cancer.
2014-04-01 | GSE31406 | GEO
Project description:We analyze by mRNA seq the in vitro decidualization of an immortalized human endometrial stromal cell line (T-HESC). As shown in our previous morphologic analysis (Anelli et al., Traffic 2022) T-HESC undergo a dramatic rearrangement (also at the mRNA level) of the entire the secretory pathway.
2022-09-28 | GSE200200 | GEO
Project description:Whole genome binding profile of SRC-2/NCOA2 in human endometrial stromal cells
2018-12-04 | GSE123246 | GEO
Project description:Our previous studies have shown that C/EBPβ plays a critical role in human endometrial stromal decidualization. In order to identify the molecular pathways regulated by C/EBPβ during decidualization, we performed gene expression profiling using RNA isolated from normal and C/EBPβ-deficient human endometrial stromal cells. The microarray results revealed that several key regulators of stromal differentiation, such as BMP2, Wnt4, IL-11Rα and STAT3, operate downstream of C/EBPβ during decidualization. Further studies revealed that STAT3 is a direct target of C/EBPβ and plays an important role in cytokine signal during the decidualization process. Gene expression profiling, using STAT3-deficient HESCs, showed an extensive overlap of pathways downstream of STAT3 and C/EBPβ during stromal cell differentiation.
2012-10-11 | GSE41473 | GEO
Project description:Our previous studies have shown that C/EBPM-NM-2 plays a critical role in human endometrial stromal decidualization. In order to identify the molecular pathways regulated by C/EBPM-NM-2 during decidualization, we performed gene expression profiling using RNA isolated from normal and C/EBPM-NM-2-deficient human endometrial stromal cells. The microarray results revealed that several key regulators of stromal differentiation, such as BMP2, Wnt4, IL-11RM-NM-1 and STAT3, operate downstream of C/EBPM-NM-2 during decidualization. Further studies revealed that STAT3 is a direct target of C/EBPM-NM-2 and plays an important role in cytokine signal during the decidualization process. Gene expression profiling, using STAT3-deficient HESCs, showed an extensive overlap of pathways downstream of STAT3 and C/EBPM-NM-2 during stromal cell differentiation. We employed a siRNA strategy to suppress C/EBPM-NM-2 or STAT3 mRNA expression in HESCs and then performed microarray analysis to identify its downstream target genes. Further, using a similar strategy, we focused on STAT3, a C/EBPM-NM-2 target gene, and identified the commone pathways downstream of both C/EBPM-NM-2 and STAT3.
2012-10-11 | E-GEOD-41473 | biostudies-arrayexpress
Project description:TRIM28 interacts with PGR and ESR1 in both human and mouse uterus to modulate estrogen and progesterone signaling. Knocking down of TRIM28 in the human endometrial stromal cells imparied decidualization in vitro. Deletion of TRIM28 from mouse uterus disrupted uterine stromal decidualization leading to infertility. Addtionally, TRIM28 deletion caused abnormal accumulation of TRIM28 postive and PGR negative cells in the stroma.
2023-06-04 | GSE205477 | GEO
Project description:TRIM28 interacts with PGR and ESR1 in both human and mouse uterus to modulate estrogen and progesterone signaling. Knocking down of TRIM28 in the human endometrial stromal cells imparied decidualization in vitro. Deletion of TRIM28 from mouse uterus disrupted uterine stromal decidualization leading to infertility. Addtionally, TRIM28 deletion caused abnormal accumulation of TRIM28 postive and PGR negative cells in the stroma.
2023-06-04 | GSE205475 | GEO
Project description:TRIM28 interacts with PGR and ESR1 in both human and mouse uterus to modulate estrogen and progesterone signaling. Knocking down of TRIM28 in the human endometrial stromal cells imparied decidualization in vitro. Deletion of TRIM28 from mouse uterus disrupted uterine stromal decidualization leading to infertility. Addtionally, TRIM28 deletion caused abnormal accumulation of TRIM28 postive and PGR negative cells in the stroma.
2023-06-04 | GSE205474 | GEO
Project description:Our previous studies have shown that bone morphogenetic protein 2 (BMP2), a morphogen belonging to the TGFM-NM-2 superfamily, is markedly induced in human primary endometrial stromal cells (HESC) as they undergo differentiation in response to steroid hormones and cAMP. WNT4 is a downstream target of BMP2 regulation in these cells. To identify the common downstream targets of BMP2 and WNT4 in human endometrial stromal cells, we performed gene expression profling of human ensometrial stromal cell transduced with BMP2 or WNT4 adenovirus. Gene expression profiling revealed that FOXO1, a forkhead family transcription factor and a known regulator of HESC differentiation, is a common downstream mediator of both BMP2 and WNT4 signaling. These studies uncovered a linear pathway involving BMP2, WNT4, and FOXO1 that operates in human endometrium to critically control decidualization. Human endometrial stromal cells were transduced with recombinant adenovirus expressing BMP2, WNT4, or a negative control GFP at MOI 50:1 in 2 ml of culture medium. After transduction for 24 h, the viral particles were removed and the cells were treated with E+P for 3 days to induce decidualization (n=3 for each treatment), pooled total RNA from these cells was then hybridized to high density affymetrix microarrays according to the Affymetrix protocol (Human Genome HG-U133 A2.0 Array) .
2013-02-08 | E-GEOD-39949 | biostudies-arrayexpress