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SUMOylation Regulates the Anti-Proliferative Gene Signature Programs of Glucocorticoid Receptor (U2Os cell line)

ABSTRACT: In addition to the glucocorticoids, the glucocorticoid receptor (GR) is regulated by post-translational modifications, including SUMOylation. We have analyzed how SUMOylation influences the activity of endogenous GR target genes and the receptor chromatin binding by using isogenic HEK293 cells expressing wild-type GR (wtGR) or SUMOylation-defective GR (GR3KR). Gene expression profiling revealed that both dexamethasone up- and down-regulated genes are affected by the GR sumoylation and that the affected genes are significantly associated with pathways of cellular proliferation and survival. The GR3KR-expressing cells proliferated more rapidly and their anti-proliferative response to dexamethasone was less pronounced than in the wtGR-expressing cells. ChIP-seq analyses indicated that the SUMOylation modulates the chromatin occupancy of GR on several loci associated with cellular growth in a fashion which parallels with their differential dexamethasone-regulated expression between the two cell lines. Moreover, genome-wide SUMO-2/3 marks, which were generally associated with active chromatin, showed markedly higher overlap with the wtGR cistrome than with the GR3KR cistrome. In sum, our results indicate that the SUMOylation does not simply repress the GR activity, but regulates the activity of the receptor in a target locus selective fashion, playing an important role in controlling the GR activity on genes influencing cell growth. Total RNA isolated from U2Os cell lines stably expressing either wild-type GR (wtGR) or SUMOylation-defective GR (GR3KR) treated with either vehicle (EtOH) or 100 nM of dexamethasone (dex) for 6h.

ORGANISM(S): Homo sapiens

SUBMITTER: Ville Paakinaho

PROVIDER: E-GEOD-48330 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Similar Datasets

SUMOylation Regulates the Anti-Proliferative Gene Signature Programs of Glucocorticoid Receptor (HEK293)

Project description:In addition to the glucocorticoids, the glucocorticoid receptor (GR) is regulated by post-translational modifications, including SUMOylation. We have analyzed how SUMOylation influences the activity of endogenous GR target genes and the receptor chromatin binding by using isogenic HEK293 cells expressing wild-type GR (wtGR) or SUMOylation-defective GR (GR3KR). Gene expression profiling revealed that both dexamethasone up- and down-regulated genes are affected by the GR sumoylation and that the affected genes are significantly associated with pathways of cellular proliferation and survival. The GR3KR-expressing cells proliferated more rapidly and their anti-proliferative response to dexamethasone was less pronounced than in the wtGR-expressing cells. ChIP-seq analyses indicated that the SUMOylation modulates the chromatin occupancy of GR on several loci associated with cellular growth in a fashion which parallels with their differential dexamethasone-regulated expression between the two cell lines. Moreover, genome-wide SUMO-2/3 marks, which were generally associated with active chromatin, showed markedly higher overlap with the wtGR cistrome than with the GR3KR cistrome. In sum, our results indicate that the SUMOylation does not simply repress the GR activity, but regulates the activity of the receptor in a target locus selective fashion, playing an important role in controlling the GR activity on genes influencing cell growth. Total RNA isolated from isogenic HEK293 cell lines stably expressing either wild-type GR (wtGR) or SUMOylation-defective GR (GR3KR) treated with either vehicle (EtOH) or 100 nM of dexamethasone (dex) for 6h. All conditions are performed in triplicate

2013-11-05 | E-GEOD-48328 | biostudies-arrayexpress

Electrophilic lipid mediator 15-deoxy-M-NM-^T12,14-prostaglandin J2 modifies glucocorticoid signaling via receptor SUMOylation

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

SUMOylation Regulates the Anti-Proliferative Gene Signature Programs of Glucocorticoid Receptor (ChIP-seq)

Project description:In addition to the glucocorticoids, the glucocorticoid receptor (GR) is regulated by post-translational modifications, including SUMOylation. We have analyzed how SUMOylation influences the activity of endogenous GR target genes and the receptor chromatin binding by using isogenic HEK293 cells expressing wild-type GR (wtGR) or SUMOylation-defective GR (GR3KR). Gene expression profiling revealed that both dexamethasone up- and down-regulated genes are affected by the GR sumoylation and that the affected genes are significantly associated with pathways of cellular proliferation and survival. The GR3KR-expressing cells proliferated more rapidly and their anti-proliferative response to dexamethasone was less pronounced than in the wtGR-expressing cells. ChIP-seq analyses indicated that the SUMOylation modulates the chromatin occupancy of GR on several loci associated with cellular growth in a fashion which parallels with their differential dexamethasone-regulated expression between the two cell lines. Moreover, genome-wide SUMO-2/3 marks, which were generally associated with active chromatin, showed markedly higher overlap with the wtGR cistrome than with the GR3KR cistrome. In sum, our results indicate that the SUMOylation does not simply repress the GR activity, but regulates the activity of the receptor in a target locus selective fashion, playing an important role in controlling the GR activity on genes influencing cell growth. Examination of GR and SUMO-2/3 binding from isogenic HEK293 cell lines stably expressing either wtGR or GR3KR, in biological duplicates, using Illumina HiSeq 2000. GR binding from control HEK293 (FRT) cell line and input sample from FRT were used as controls for GR. Sequenced IgG sample from FRT cell line was used as control for SUMO-2/3

2013-11-05 | E-GEOD-48374 | biostudies-arrayexpress

SUMOylation Regulates the Anti-Proliferative Gene Signature Programs of Glucocorticoid Receptor (U2Os cell line)

2013-11-05 | GSE48330 | GEO

SUMOylation Regulates the Anti-Proliferative Gene Signature Programs of Glucocorticoid Receptor (HEK293)

2013-11-05 | GSE48328 | GEO

SUMOylation Regulates the Anti-Proliferative Gene Signature Programs of Glucocorticoid Receptor (ChIP-seq)

2013-11-05 | GSE48374 | GEO

Genome-wide analysis of androgen receptor (AR) SUMOylation effects on gene expression (HEK293).

Project description:Androgen receptor (AR) plays an important regulatory role during prostate cancer development. ARM-bM-^@M-^Ys transcriptional activity is regulated by androgenic ligands, but also by post-translational modifications. To study the role of the AR SUMOylation in genuine chromatin environment, we compared androgen-regulated gene expression and AR chromatin occupancy in PC-3 prostate cancer and HEK293 cell lines stably expressing wild-type (wt) or SUMOylation site-mutated AR (AR-K386R,K520R). Our genome-wide gene expression analyses reveal that the SUMOylation modulates the AR function in a target gene and pathway selective manner. The transcripts that are differentially regulated by androgen and SUMOylation are linked to cellular movement, cell death, cellular proliferation, cellular development and cell cycle. In line with these data, SUMOylation mutant AR cells proliferate faster and are more sensitive to apoptosis. Moreover, ChIP-seq analyses show that the SUMOylation modulates the chromatin occupancy of AR on many loci in a fashion that parallels with their differential androgen-regulated expression. De novo motif analyses show that other transcription factor-binding motifs are differentially enriched at the wtAR- and the AR-K386R,K520R-preferred genomic binding positions. Taken together, our data indicate that SUMOylation does not simply repress the AR activity, but it regulates ARM-bM-^@M-^Ys interaction with the chromatin and the receptorM-bM-^@M-^Ys target gene selection. Isogenic HEK293 cells stably expressing wild-type AR (wtAR) or SUMOylation-defective AR (AR-K2R) were treated 24 h with 10 nM R1881 or vehicle (EtOH). All conditions were performed in triplicate. The effect on gene expression was assessed by microarray.

2014-07-03 | E-GEOD-54137 | biostudies-arrayexpress

Genome-wide analysis of androgen receptor (AR) SUMOylation effects on gene expression (PC-3).

Project description:Androgen receptor (AR) plays an important regulatory role during prostate cancer development. ARM-bM-^@M-^Ys transcriptional activity is regulated by androgenic ligands, but also by post-translational modifications. To study the role of the AR SUMOylation in genuine chromatin environment, we compared androgen-regulated gene expression and AR chromatin occupancy in PC-3 prostate cancer and HEK293 cell lines stably expressing wild-type (wt) or SUMOylation site-mutated AR (AR-K386R,K520R). Our genome-wide gene expression analyses reveal that the SUMOylation modulates the AR function in a target gene and pathway selective manner. The transcripts that are differentially regulated by androgen and SUMOylation are linked to cellular movement, cell death, cellular proliferation, cellular development and cell cycle. In line with these data, SUMOylation mutant AR cells proliferate faster and are more sensitive to apoptosis. Moreover, ChIP-seq analyses show that the SUMOylation modulates the chromatin occupancy of AR on many loci in a fashion that parallels with their differential androgen-regulated expression. De novo motif analyses show that other transcription factor-binding motifs are differentially enriched at the wtAR- and the AR-K386R,K520R-preferred genomic binding positions. Taken together, our data indicate that SUMOylation does not simply repress the AR activity, but it regulates ARM-bM-^@M-^Ys interaction with the chromatin and the receptorM-bM-^@M-^Ys target gene selection. PC-3 cells stably expressing wild-type AR (wtAR) or SUMOylation-defective AR (AR-K2R) were treated 16 h with 10 nM R1881 or vehicle (EtOH). All conditions were performed in triplicate. The effect on gene expression was assessed by microarray.

2014-07-03 | E-GEOD-54104 | biostudies-arrayexpress

Electrophilic lipid mediator 15-deoxy-Δ12,14-prostaglandin J2 modifies glucocorticoid signaling via receptor SUMOylation

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

Studying enhancer activity by FAIRE-STARR-seq in the U2OS-GR and the U2OS-AR cells upon hormone treatment

Project description:To quantify functional enhancers, we performed STARR-seq (Self-Transcribing Active Regulatory Region sequencing) in the U2OS-GR and the U2OS-AR cell lines (derived from U2OS ATTC:HTB-96, stably transfected with an expression construct for rat GR or human AR, respectively). U2OS-GR cells were treated with dexamethasone (1 µM) or vehicle (ethanol) for 14 hours. U2OS-AR cells were treated with R1881 (5 nM) or vehicle (DMSO) for 14 hours. To limit the number of putative enhancers, the STARR library contained genomic regions isolated by FAIRE (Formaldehyde Assisted Isolation of Regulatory Elements) from dexamethasone-treated U2OS-GR cells to include regions that gain accessibility upon GR activation. We added unique molecular identifiers (UMIs) during the reverse transcription stage to facilitate quantitative measurements of enhancer activity for each fragment. The UMI for each read is present within the sequence identifier line (directly following the y coordinate and separated by a ':') of the fastq files.

2021-03-09 | E-MTAB-9614 | biostudies-arrayexpress

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