Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Unliganded estrogen receptor alpha regulates vascular cell function and gene expression

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51535 | GEO | 2016/11/22

SECONDARY ACCESSION(S): PRJNA223389

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

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.

2014-06-30 | GSE57804 | GEO

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

2014-06-30 | GSE52351 | GEO

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

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

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

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

Differences in the Transcriptional Response to Fulvestrant and Estrogen Deprivation in ER-Positive Breast Cancer

Project description:Aromatase inhibitors are first-line postmenopausal agents for estrogen receptor alpha (ERa)-positive breast cancer. However, there is considerable response heterogeneity and women frequently relapse. Estrogen deprivation does not completely arrest ERa activity, and transactivation of the unliganded receptor may continue through cross-talk with growth factor pathways. In contrast with aromatase inhibitors, the selective ER downregulator fulvestrant also abrogates ligand-independent ERa activity. The benefit of fulvestrant as an alternative, combination, or sequential therapy to aromatase inhibitor has been reported, but molecular mechanisms underpinning its relative efficacy remain unclear and biomarkers for patient selection are lacking. This study demonstrates, for the first time, that the overall transcriptional response to fulvestrant is of greater magnitude than estrogen deprivation, consistent with its clinical efficacy and more complete blockade of estrogenic signaling. Using a robust integrative approach, we identify a subset of genes differentially affected by fulvestrant that comprises distinct biologic networks, correlates with antiproliferative response, and has potential utility as predictive biomarkers for fulvestrant. Global gene expression profiles from ERα-positive breast carcinomas before and during presurgical treatment with fulvestrant (n = 38) or anastrozole (n = 81), and corresponding in vitro models, were compared. Transcripts responding differently to fulvestrant and estrogen deprivation were identified and integrated using Gene Ontology, pathway and network analyses to evaluate their potential significance. --------------------------------- This represents the data for fulvestrant only

2015-08-07 | E-GEOD-71791 | biostudies-arrayexpress

Differences in the Transcriptional Response to Fulvestrant and Estrogen Deprivation in ER-Positive Breast Cancer

2015-08-07 | GSE71791 | GEO

Expression data from endthelial cells in ductus arteriosus and aorta in rat fetuses or neonates

Project description:Endothelial cells (Ecs) lining the blood vessels have been known to have a variety of functions and play a central role in homeostasis of the circulatory system. Since ductus arteriosus (DA) has unique characteristics comparing other vessels, we hypothesized that ECs were the primary target to investigate the molecular mechanisms of DA-specific vasoconstriction and vascular remodeling. Using fluorescence activated cell sorter, we isolated ECs from pooled tissues from the DA or the aorta of Wistar rat fetuses on the 21st day of gestation (e21) or 30 minutes after birth (day0). We prepared 3 sets of ECs in each tissues and time points. We aimed to compare the gene profiles of DA and the aorta at each developmental stage.

2013-10-01 | E-GEOD-40500 | biostudies-arrayexpress

The dual function of JmjC domain-containing protein KDM5C in both gene transcriptional activation and repression promotes breast cancer cell growth and tumorigenesis [RNA-seq]

Project description:Emerging evidence suggested that epigenetic regulators can exhibit both co-activator and co-repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in cellular contexts remains elusive. Here, we reported that KDM5C, a repressive histone demethylase, is unexpectedly required for estrogen/estrogen receptor alpha (ERa)-induced gene transcriptional activation to promote cell proliferation, while it suppresses the expression of type I interferons (IFNs) and interferon-stimulated genes (ISGs) to escape from immuno-surveillance. KDM5C-interacting protein, ZMYND8, is found to be accompanied with KDM5C in regulation of both subsets of genes. Mechanistically, during estrogen/ERa-induced gene transcriptional activation, ERa interacts and recruits KDM5C/ZMYND8 to active enhancers, where ERa masks KDM5C’s demethylase activity towards H3K4me2/3, converting KDM5C from a co-repressor to a co-activator. Furthermore, KDM5C and ZMYND8 are found to recruit the P-TEFb complex in a cooperative manner to activate estrogen/ERa-target genes. In contrast, KDM5C/ZMYND8 represses type I IFNs and ISGs through directly interfering TBK1 phosphorylation in an enzymatic-dependent manner. The combinatory effects of KDM5C’s dual activities in regulation of genes involved in both cell proliferation and immuno-escape lead to breast cancer cell proliferation in vitro and xenograft growth in mice. Taken together, we revealed a mechanism by which a repressive epigenetic regulator can be converted to a co-activator under specific signal cues to regulate specific gene programs, and the dual nature as both a co-repressor and co-activator together contributes to cancer development.

2021-03-17 | GSE141987 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data