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Aorta- and liver-specific ERalpha-binding patterns and gene regulation by estrogen (ChIP-seq)

ABSTRACT: Estrogen has vascular protective effects in premenopausal women and in women under 60 receiving hormone replacement therapy. However, estrogen also increases risks of breast and uterine cancers and of venous thromboses linked to upregulation of coagulation factors in the liver. In mouse models, the vasoprotective effects of estrogen are mediated by the estrogen receptor alpha (ERa) transcription factor. Here, through next generation sequencing approaches, we show that almost all of the genes regulated by 17-b-estradiol (E2) differ between mouse aorta and mouse liver, and that this is associated with a distinct genomewide distribution of ERa on chromatin. Bioinformatic analysis of E2-regulated promoters and ERa binding site sequences identify several transcription factors that may determine the tissue specificity of ERa binding and E2-regulated genes, including the enrichment of NFkB, AML1 and AP-1 sites in the promoters of E2 downregulated inflammatory genes in aorta but not liver. The possible vascular-specific functions of these factors suggests ways in which the protective effects of estrogen could be promoted in the vasculature without incurring negative effects in other tissues. Our results also highlight the likely importance of rapid signaling of membrane-associated ERa to cellular kinases (altering the activities of transcription factors other than ER itself) in determining tissue specific transcriptional responses to estrogen.

ORGANISM(S): Mus musculus

PROVIDER: GSE52351 | GEO | 2014/06/30

SECONDARY ACCESSION(S): PRJNA227460

REPOSITORIES: GEO

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Aorta- and liver-specific ERalpha binding patterns and gene regulation by estrogen

Project description:Estrogen has vascular protective effects in premenopausal women and in women under 60 receiving hormone replacement therapy. However, estrogen also increases risks of breast and uterine cancers and of venous thromboses linked to upregulation of coagulation factors in the liver. In mouse models, the vasoprotective effects of estrogen are mediated by the estrogen receptor alpha (ERa) transcription factor. Here, through next generation sequencing approaches, we show that almost all of the genes regulated by 17-b-estradiol (E2) differ between mouse aorta and mouse liver, and that this is associated with a distinct genomewide distribution of ERa on chromatin. Bioinformatic analysis of E2-regulated promoters and ERa binding site sequences identify several transcription factors that may determine the tissue specificity of ERa binding and E2-regulated genes, including the enrichment of NFkB, AML1 and AP-1 sites in the promoters of E2 downregulated inflammatory genes in aorta but not liver. The possible vascular-specific functions of these factors suggests ways in which the protective effects of estrogen could be promoted in the vasculature without incurring negative effects in other tissues. Our results also highlight the likely importance of rapid signaling of membrane-associated ERa to cellular kinases (altering the activities of transcription factors other than ER itself) in determining tissue specific transcriptional responses to estrogen. The aortas or liver fragments of wild-type C57/BL6 mice were incubated ex vivo with 10nM E2 or ethanol vehicle for 4 hours before harvesting for RNA collection. Each condition was performed with two biological replicates, and each replicate contained aortas or liver fragments from 4 mice.

2014-06-30 | E-GEOD-57804 | biostudies-arrayexpress

Aorta- and liver-specific ERalpha-binding patterns and gene regulation by estrogen

2014-06-30 | GSE57804 | GEO

Aorta- and liver-specific ERalpha binding patterns and gene regulation by estrogen (ChIP-seq)

Project description:Estrogen has vascular protective effects in premenopausal women and in women under 60 receiving hormone replacement therapy. However, estrogen also increases risks of breast and uterine cancers and of venous thromboses linked to upregulation of coagulation factors in the liver. In mouse models, the vasoprotective effects of estrogen are mediated by the estrogen receptor alpha (ERa) transcription factor. Here, through next generation sequencing approaches, we show that almost all of the genes regulated by 17-b-estradiol (E2) differ between mouse aorta and mouse liver, and that this is associated with a distinct genomewide distribution of ERa on chromatin. Bioinformatic analysis of E2-regulated promoters and ERa binding site sequences identify several transcription factors that may determine the tissue specificity of ERa binding and E2-regulated genes, including the enrichment of NFkB, AML1 and AP-1 sites in the promoters of E2 downregulated inflammatory genes in aorta but not liver. The possible vascular-specific functions of these factors suggests ways in which the protective effects of estrogen could be promoted in the vasculature without incurring negative effects in other tissues. Our results also highlight the likely importance of rapid signaling of membrane-associated ERa to cellular kinases (altering the activities of transcription factors other than ER itself) in determining tissue specific transcriptional responses to estrogen. The aortas or liver fragments of wild-type C57/BL6 mice were incubated ex vivo with 10nM E2 or ethanol vehicle for 45 minutes before formaldehyde fixation, harvesting of chromatin & ChIP with anti- mouse estrogen receptor alpha antibodies. Each condition was performed with two biological replicates, and each replicate contained aortas or liver fragments from 5 mice.

2014-06-30 | E-GEOD-52351 | biostudies-arrayexpress

Unliganded estrogen receptor alpha regulates vascular cell function and gene expression

Project description:Estrogen receptor alpha (ERa) has generally been thought to be transcriptionally inactive until it binds estrogen. Here we show that unliganded ERa, far from being transcriptionally inert, regulates a large number of genes both in vascular endothelial cells (ECs) and in mouse aorta. The genes regulated by unliganded ERa in the aorta (largely composed of smooth muscle cells) differ from those in ECs, and aorta- and EC-regulated promoters show enrichment in binding sites for distinct sets of transcription factors. In vitro, the presence of unliganded ERa decreases the migration and proliferation of ECs, and also increases proliferation of SMCs. Consistent with these effects on individual cells in vitro, mice lacking ERa, in the absence of estrogen, show significantly less SMC proliferation and medial thickening after carotid artery wire injury than ER intact mice. The effects of unliganded ERa on vascular gene expression, cell function in vitro and vascular injury responses in vivo are all reversed by the addition of estrogen. Taken together, these results indicate that unliganded ERa regulates vascular gene expression, vascular cell function, and vascular injury responses, and that the cardiovascular protective effects of estrogen may largely be due to the reversal of these effects of unliganded ERa. These results have important implications for the vascular health of men and post-menopausal women with vascular ERa and low circulating levels of estrogen. This study also raises the possibility that the steroid receptor family could have substantial hormone-independent functions in the vasculature and in other tissues.

2016-11-22 | GSE51535 | GEO

ER alpha rapid signaling is required for estrogen induced proliferation and migration of vascular endothelial cells

Project description:Estrogen receptor alpha (ERa) is required for the protective effects of 17-beta-estradiol (E2, the active, endogenous form of estrogen) after vascular injury or in atherosclerosis. E2-bound ERa can function as a transcription factor which binds directly to chromatin (the genomic pathway). Some ERa is also associated with the plasma membrane and, when bound by E2, activates cellular kinases, including PI3K, Akt and ERK (the rapid signaling pathway). Rapid signaling is mediated by interaction between ERa and the adaptor molecule striatin. Here we identify a triple point mutation (AA 231,233 & 234 KRR->AAA) of full length ERa that blocks its association with striatin and eliminates its ability to perform rapid signaling (without affecting its ability to perform genomic signaling). We have created stably-transfected human vascular endothelial cell lines expressing either WT ERa (WT ECs) or KRR mutant ERa (KRR ECs), and use these cells to show that rapid signaling through ERa is required for the proper regulation of most E2-regulated genes (the data presented in this record), and also for the ability of E2 to stimulate EC migration and proliferation and to inhibit inflammatory monocyte adhesion to ECs. Human Eahy 926 stable cell lines carrying a full length wild-type human estrogen receptor alpha (ERa) expression vector (WT ECs) or a full length KRR mutant ERa expression vector (KRR ECs, where the KRR mutant ERa is deficient in rapid signaling) were treated with or without 17-b-estradiol (E2) for 16 hrs. RNA from 3 bioligical replicates per condition was harvested and used to probe Illumina bead arrays.

2016-03-22 | E-GEOD-72180 | biostudies-arrayexpress

ER alpha rapid signaling is required for estrogen induced proliferation and migration of vascular endothelial cells

2016-03-22 | GSE72180 | GEO

Endothelial ER-alpha Promotes Glucose Tolerance by Enhancing Endothelial Insulin Transport to Skeletal Muscle

Project description:Human aortic endothelial cells were treated with vehicle or estradiol. Immunoprecipitation was then performed with anti-estrogen receptor alpha antibody or mock IgG, and liquid chromatography/tandem mass spectrometry was done. 996859: Mock-IgG-Veh#1; 996860: Mock-IgG-E2#1; 996861: ERa-Veh#1; 996862: ERa-E2#1; 996863: Mock-IgG-Veh#2; 996864: Mock-IgG-E2#2; 996865: ERa-Veh#2; 996866: ERa-E2#2; 996867: Mock-IgG-Veh#3; 996868: Mock-IgG-E2#3; 996869: ERa-Veh#3; 996870: ERa-E2#3

2023-01-19 | MSV000091095 | MassIVE

Osteoclastic estrogen receptor alpha mediates the osteoprotective estrogen action through Fas ligand signaling

Project description:Estrogen clearly prevents osteoporotic bone loss by attenuating bone resorption. The molecular basis of how this is accomplished, however, remains elusive. Here we report a critical role of osteoclastic ERa in mediating estrogen action on bone in females. We selectively ablated ERa in differentiated osteoclasts (ERa dOc/dOc). ERa dOc/dOc females, but not males, exhibited clear trabecular bone loss, similar to the osteoporotic bone phenotype in post-menopausal women. Recovery of bone loss by estrogen treatment of the ovariectomized ERa dOc/dOc females was ineffective in the trabecular areas of the long bones and lumbar vertebral bodies. Osteoclastic apoptosis, induced by estrogen, occurred simultaneously with up-regulation of Fas ligand (FasL) expression in intact trabecular bones of ERa +/+mice, but not in ERa dOc/dOc mice. ERa was also required for similar effects of estrogen and tamoxifen in cultured osteoclasts. These findings suggest that the osteoprotective actions of estrogen and SERMS are mediated at least in part through osteoclastic ERa in trabecular bone; and the life span of mature osteoclasts is regulated through activation of the Fas/FasL system. Keywords: Study about estrogen response of osteoclast-specific estrogen receptor alpha mice

2007-06-01 | GSE7798 | GEO

Transcription profiling of mouse ERa abalated differentiated osteoclasts

Project description:Estrogen clearly prevents osteoporotic bone loss by attenuating bone resorption. The molecular basis of how this is accomplished, however, remains elusive. Here we report a critical role of osteoclastic ERa in mediating estrogen action on bone in females. We selectively ablated ERa in differentiated osteoclasts (ERa dOc/dOc). ERa dOc/dOc females, but not males, exhibited clear trabecular bone loss, similar to the osteoporotic bone phenotype in post-menopausal women. Recovery of bone loss by estrogen treatment of the ovariectomized ERa dOc/dOc females was ineffective in the trabecular areas of the long bones and lumbar vertebral bodies. Osteoclastic apoptosis, induced by estrogen, occurred simultaneously with up-regulation of Fas ligand (FasL) expression in intact trabecular bones of ERa +/+mice, but not in ERa dOc/dOc mice. ERa was also required for similar effects of estrogen and tamoxifen in cultured osteoclasts. These findings suggest that the osteoprotective actions of estrogen and SERMS are mediated at least in part through osteoclastic ERa in trabecular bone; and the life span of mature osteoclasts is regulated through activation of the Fas/FasL system. Experiment Overall Design: Wild type and osteoclast-specific Estrogen Receptor alpha knock-out mice were ovariectomized. The number of both genotypes of mice was eight. The mice of each genotypes were divided to vehicle control and estrogen treated group. Four hours after chemical treatment, the distal 5 mm of the left femurs were harvested after sacrificing by cervical dislocation and total RNAs were purified for Affymetix GeneChip microarray analysis without pooling. Therefore, this experiment consists of four groups with four replicates per group.

2008-06-15 | E-GEOD-7798 | biostudies-arrayexpress

Genome-wide analysis of Estrogen Receptor-mediated response to acute Estradiol treatment in liver (expression)

Project description:Estrogen-based treatments have numerous extra-reproductive effects. On the one hand, they have protective metabolic actions against abdominal fat accumulation, type 2 diabetes, liver steatosis,â¦ But, on the other hand, the oral route of administration, presumably due to a hepatic impact on liver-derived coagulation factors, appears to increase risks of venous thrombosis and pulmonary embolism. The characterization of liver genes expression regulations by these hormones thereby appears of utmost interest, but the estrogen-sensitive transcriptome of liver and ER cistrome was so far explored under chronic hormonal treatment. To explore the early steps of these mechanisms, we determined here the short-term changes in liver transcriptional responses to acute E2 administration, and aimed to characterize the mechanisms allowing these programs to be engaged. Collectively, through the comparison of mice expressing or not ER, our data demonstrate that acute administration of E2 provokes genes expression variations which fit with a crucial role of ER in the prevention of liver steatosis in mice fed with a high fat diet by E2. They also evidenced higher proportion of ER binding sites (BSs) located at the direct vicinity (distance <3kb) of regulated genes than what is determined in human cancer cell models. Besides this specific aspect of ER cistrome in vivo, we unexpectedly found that 40 % of the BSs of the pioneer factor Foxa2 were dependent upon the expression of ER that indirectly influences the distribution of the nucleosomes harbouring a dimethylated H3K4 around these Foxa2 sites. Analysis of estrogen-sensitive and estrogen receptor (ER)-dependent transcriptomes in livers from wild-type or ERKO mice.

2016-05-13 | E-GEOD-70329 | biostudies-arrayexpress

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