Physiological glucocorticoid receptor activation programs key cell phenotypes and functional epigenomic patterns in human fibroblasts [TBS]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE210303 | GEO | 2022/08/15
REPOSITORIES: GEO
Similar Datasets
Project description:Chronic environmental stress can profoundly impact cell and body function. While the underlying mechanisms are poorly understood, epigenetics has emerged as a key link between environment and health. The genomic effects of stress are thought to be mediated by the action of glucocorticoid stress hormones, primarily cortisol in humans, which act via the glucocorticoid receptor (GR). To dissect how physiological GR activation influences epigenetic and cell states, human fibroblasts underwent prolonged exposure to physiological stress levels of cortisol and/or a selective GR antagonist. Cortisol was found to drive robust changes in cell proliferation, migration, and morphology, which were abrogated by concomitant GR blockade. These GR-driven phenotypes were accompanied by widespread, yet genomic context-dependent, changes in DNA methylation and mRNA expression involving genes with known roles in cell proliferation and migration. These findings provide novel insights into how chronic stress-driven functional epigenomic patterns become established to shape key cell phenotypes.
2022-08-15 | GSE210302 | GEO
Project description:Chronic environmental stress can profoundly impact cell and body function. While the underlying mechanisms are poorly understood, epigenetics has emerged as a key link between environment and health. The genomic effects of stress are thought to be mediated by the action of glucocorticoid stress hormones, primarily cortisol in humans, which act via the glucocorticoid receptor (GR). To dissect how physiological GR activation influences epigenetic and cell states, human fibroblasts underwent prolonged exposure to physiological stress levels of cortisol and/or a selective GR antagonist. Cortisol was found to drive robust changes in cell proliferation, migration, and morphology, which were abrogated by concomitant GR blockade. These GR-driven phenotypes were accompanied by widespread, yet genomic context-dependent, changes in DNA methylation and mRNA expression involving genes with known roles in cell proliferation and migration. These findings provide novel insights into how chronic stress-driven functional epigenomic patterns become established to shape key cell phenotypes.
2022-08-15 | GSE210301 | GEO
Project description:Glucocorticoids act through the glucocorticoid receptor (GR), a ligand activated transcription factor, to modulate gene expression profiles in target cells and tissues. The principal physiological glucocorticoid in humans, cortisol, is released in a pulsatile fashion from the adrenal gland, which results in oscillations in blood concentrations, with a period of 1 - 2 hours. The biological consequence of fluctuating cortisol concentrations has not been explored. To identify the role of cortisol concentration oscillations for target cell response a flow-through cell culture system was developed. Transcription profiling was performed in the absence and presence of cortisol. Cells were exposed to constant cortisol levels of 100ng/ml or 200 ng/ml or oscillating cortisol concentrations.
2010-07-10 | E-MEXP-2447 | biostudies-arrayexpress
Project description:This a model from the article:
Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal
axis model reveals bistability.
Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. Theor Biol Med Model
2007 Feb 14;4:8 17300722
,
Abstract:
BACKGROUND: The body's primary stress management system is the hypothalamic
pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental
challenge to maintain homeostasis in part by controlling the body's cortisol
level. Dysregulation of the HPA axis is implicated in numerous stress-related
diseases. RESULTS: We developed a structured model of the HPA axis that includes
the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of
pituitary GR synthesis. The nonlinear effect arises from the fact that GR
homodimerizes after cortisol activation and induces its own synthesis in the
pituitary. This homodimerization makes possible two stable steady states (low
and high) and one unstable state of cortisol production resulting in bistability
of the HPA axis. In this model, low GR concentration represents the normal
steady state, and high GR concentration represents a dysregulated steady state.
A short stress in the normal steady state produces a small perturbation in the
GR concentration that quickly returns to normal levels. Long, repeated stress
produces persistent and high GR concentration that does not return to baseline
forcing the HPA axis to an alternate steady state. One consequence of increased
steady state GR is reduced steady state cortisol, which has been observed in
some stress related disorders such as Chronic Fatigue Syndrome (CFS).
CONCLUSION: Inclusion of pituitary GR expression resulted in a biologically
plausible model of HPA axis bistability and hypocortisolism. High GR
concentration enhanced cortisol negative feedback on the hypothalamus and forced
the HPA axis into an alternative, low cortisol state. This model can be used to
explore mechanisms underlying disorders of the HPA axis.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. (2007) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1006230036 | BioModels
Project description:This a model from the article:
Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal
axis model reveals bistability.
Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. Theor Biol Med Model
2007 Feb 14;4:8 17300722
,
Abstract:
BACKGROUND: The body's primary stress management system is the hypothalamic
pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental
challenge to maintain homeostasis in part by controlling the body's cortisol
level. Dysregulation of the HPA axis is implicated in numerous stress-related
diseases. RESULTS: We developed a structured model of the HPA axis that includes
the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of
pituitary GR synthesis. The nonlinear effect arises from the fact that GR
homodimerizes after cortisol activation and induces its own synthesis in the
pituitary. This homodimerization makes possible two stable steady states (low
and high) and one unstable state of cortisol production resulting in bistability
of the HPA axis. In this model, low GR concentration represents the normal
steady state, and high GR concentration represents a dysregulated steady state.
A short stress in the normal steady state produces a small perturbation in the
GR concentration that quickly returns to normal levels. Long, repeated stress
produces persistent and high GR concentration that does not return to baseline
forcing the HPA axis to an alternate steady state. One consequence of increased
steady state GR is reduced steady state cortisol, which has been observed in
some stress related disorders such as Chronic Fatigue Syndrome (CFS).
CONCLUSION: Inclusion of pituitary GR expression resulted in a biologically
plausible model of HPA axis bistability and hypocortisolism. High GR
concentration enhanced cortisol negative feedback on the hypothalamus and forced
the HPA axis into an alternative, low cortisol state. This model can be used to
explore mechanisms underlying disorders of the HPA axis.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. (2007) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1006230111 | BioModels
Project description:Stress induced elevation in plasma cortisol levels is shown to be involved in the metabolic re-adjustments to stress but the genetic basis of this response is still unclear. Cortisol signaling in teleosts is thought to be mediated predominantly by the glucocorticoid receptor (GR), a ligand-bound transcription factor and previous studies have shown that RU486, a GR antagonist offsets corticosteroid signaling in teleosts. In order to elucidate the genetic basis of GR-mediated metabolic re-adjustments, we exposed in vitro primary culture of trout hepatocytes to cortisol (100 ng/ml; stressed levels) or RU486 (1000 ng/ml) or a combination of both (RU486 + Cortisol), and analyzed the transcriptional responses using a low density custom-made targeted trout cDNA array. These results were further validated using quantitative real-time PCR. Cortisol treatment significantly increased glucose production in hepatocytes and this response is blocked by RU486 suggesting the activation of GR-mediated corticosteroid signaling. Cortisol treatment significantly modulated the transcript abundance of several genes, previously shown to be involved in molecular and biochemical responses to stress and most of these effects are abolished by RU486, suggesting GR-mediated effects. In addition, cortisol treatment affected key genes involved in reproduction supporting previous findings on inhibitory effects of cortisol on reproduction. Taken together, our results provide evidence on the transcriptional changes involved in cortisol signaling in response to stress. Keywords: cDNA microarray, RU486, Cortisol, GR signaling, rainbow trout, hepatocytes
2007-05-02 | GSE7671 | GEO
Project description:Chronic early life stress increases adult susceptibility to numerous health problems linked to chronic inflammation. One way that this may occur is via glucocorticoid-induced developmental programming. To gain insight into such programming we treated zebrafish embryos with 1 micromolar cortisol and examined the effects on larvae. Treated larvae had elevated whole-body cortisol and glucocorticoid signaling, and up-regulated genes associated with defense response and immune system processes. 6 samples total were analyzed. 3 DMSO controls, and 3 cortisol treated (1 micromolar).
2016-06-01 | E-GEOD-80221 | biostudies-arrayexpress
Project description:Cortisol, the central stress hormone in humans, activates the glucocorticoid receptor (GR). Anti-inflammatory effects are the most important pharmaceutical effects mediated by the GR. Inasmuch as electrophilic cyclopentenone prostaglandin 15-deoxy-M-NM-^T12,14-prostaglandin J2 (15d-PGJ2) has potent anti-inflammatory properties and activates the SUMOylation pathway, we have investigated the effect of 15d-PGJ2 on glucocorticoid signaling and receptor SUMOylation. To this end, we studied isogenic HEK293 cells expressing either wild-type GR or SUMOylation-defective GR. Interestingly, 15d-PGJ2 triggered SUMO-2/3 modification in the primary SUMOylation sites of the GR. Gene expression profiling and pathway analyses indicate that 15d-PGJ2 inhibits GR signaling in a genome-wide fashion that is significantly dependent on the GR SUMOylation sites. Chromatin immunoprecipitation assays showed that the repressive effect of 15d-PGJ2 on GR target gene expression occurs in parallel with the inhibition of receptor binding to the target gene chromatin. Furthermore, depletion of the sole SUMO E2 conjugase UBC9 from HEK293 cells confirmed the involvement of active SUMOylation in the regulatory process. Taken together, our data indicate that GR SUMOylation modulates the glucocorticoid signaling during acute cell stress. Our data also suggest that GR SUMOylation modulates crosstalk of the glucocorticoid signaling with other transcription factors that are responsive to cell stress. Total RNA isolated from isogenic HEK293 cell lines stably expressing either wild-type GR (wtGR) or SUMOylation-defective GR (GR3KR) treated with 100 nM of dexamethasone (dex) in the presence or absence of 5 M-BM-5M 15d-PGJ2 for 6h. All conditions are performed in triplicate
2014-06-30 | E-GEOD-54087 | biostudies-arrayexpress
Project description:Cortisol, the central stress hormone in humans, activates the glucocorticoid receptor (GR). Anti-inflammatory effects are the most important pharmaceutical effects mediated by the GR. Inasmuch as electrophilic cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has potent anti-inflammatory properties and activates the SUMOylation pathway, we have investigated the effect of 15d-PGJ2 on glucocorticoid signaling and receptor SUMOylation. To this end, we studied isogenic HEK293 cells expressing either wild-type GR or SUMOylation-defective GR. Interestingly, 15d-PGJ2 triggered SUMO-2/3 modification in the primary SUMOylation sites of the GR. Gene expression profiling and pathway analyses indicate that 15d-PGJ2 inhibits GR signaling in a genome-wide fashion that is significantly dependent on the GR SUMOylation sites. Chromatin immunoprecipitation assays showed that the repressive effect of 15d-PGJ2 on GR target gene expression occurs in parallel with the inhibition of receptor binding to the target gene chromatin. Furthermore, depletion of the sole SUMO E2 conjugase UBC9 from HEK293 cells confirmed the involvement of active SUMOylation in the regulatory process. Taken together, our data indicate that GR SUMOylation modulates the glucocorticoid signaling during acute cell stress. Our data also suggest that GR SUMOylation modulates crosstalk of the glucocorticoid signaling with other transcription factors that are responsive to cell stress.
2014-06-30 | GSE54087 | GEO
Project description:Chronic early life stress can affect development of the neuroendocrine stress system, leading to its persistent dysregulation and consequently increased disease risk in adulthood. One contributing factor is thought to be epigenetic programming in response to chronic glucocorticoid exposure during early development. We have previously shown that zebrafish embryos treated chronically with cortisol develop into adults with constitutively elevated whole body cortisol and aberrant immune gene expression. The objective of the experiments reported here was to further characterize the phenotype of those adults. We find that adult zebrafish derived from cortisol-treated embryos have aberrant cortisol tissue distribution and dynamics, which correlate with differential transcriptional activity of key glucocorticoid-responsive regulatory genes klf9 and fkbp5 in blood and brain.
2019-10-28 | GSE137987 | GEO