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SUMOylation inhibition potentiates the glucocorticoid receptor to program growth arrest of acute lymphoblastic leukemia cells (ATAC-seq)

ABSTRACT: Glucocorticoids (GCs) are a crucial component of effective treatment for acute lymphoblastic leukemia (ALL). GCs exert their functions through the glucocorticoid receptor (GR), a ligand-activated transcription factor (TF). Chromatin occupancy, chromatin-protein networks and gene programmes of GR are regulated by SUMOylation, which has therapeutic implications in other hematomalignancies. To unravel the GR-SUMO crosstalk in ALL, we induced a hypoSUMOylated state in NALM6 ALL cells with a SUMOylation inhibitor (ML-792). Genome-wide profiling of GR and SUMO binding and chromatin accessibility revealed that hypoSUMOylation augmented GR chromatin occupancy and altered chromatin openness upon dexamethasone (Dex) exposure. Association with transcriptome data indicated that on the novel binding sites GR predominantly suppressed target gene expression. Chromatin-proteomic analyses identified a substantial number of shared TFs and coregulators associated with chromatin-bound GR and SUMO. The chromatin-protein network of GR contained several TFs with corresponding binding motifs found on GR-adjacent chromatin sites, implying their simultaneous presence on chromatin. Cell cycle and proliferation analyses indicated that hypoSUMOylation potentiated Dex-induced cell cycle arrest and suppressed NALM6 cell proliferation, complementing the significant expression changes of cell cycle-related genes in our transcriptome data. Our work provides a valuable resource of GR chromatin partners and implies potential for targeting SUMOylation to increase sensitivity to GCs in ALL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233550 | GEO | 2025/01/20

REPOSITORIES: GEO

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SUMOylation inhibition potentiates the glucocorticoid receptor to program growth arrest of acute lymphoblastic leukemia cells (RNA-seq)

Project description:Glucocorticoids (GCs) are a crucial component of effective treatment for acute lymphoblastic leukemia (ALL). GCs exert their functions through the glucocorticoid receptor (GR), a ligand-activated transcription factor (TF). Chromatin occupancy, chromatin-protein networks and gene programmes of GR are regulated by SUMOylation, which has therapeutic implications in other hematomalignancies. To unravel the GR-SUMO crosstalk in ALL, we induced a hypoSUMOylated state in NALM6 ALL cells with a SUMOylation inhibitor (ML-792). Genome-wide profiling of GR and SUMO binding and chromatin accessibility revealed that hypoSUMOylation augmented GR chromatin occupancy and altered chromatin openness upon dexamethasone (Dex) exposure. Association with transcriptome data indicated that on the novel binding sites GR predominantly suppressed target gene expression. Chromatin-proteomic analyses identified a substantial number of shared TFs and coregulators associated with chromatin-bound GR and SUMO. The chromatin-protein network of GR contained several TFs with corresponding binding motifs found on GR-adjacent chromatin sites, implying their simultaneous presence on chromatin. Cell cycle and proliferation analyses indicated that hypoSUMOylation potentiated Dex-induced cell cycle arrest and suppressed NALM6 cell proliferation, complementing the significant expression changes of cell cycle-related genes in our transcriptome data. Our work provides a valuable resource of GR chromatin partners and implies potential for targeting SUMOylation to increase sensitivity to GCs in ALL.

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SUMOylation inhibition potentiates the glucocorticoid receptor to program growth arrest of acute lymphoblastic leukemia cells (ChIP-seq)

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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 (U2Os cell line)

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 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.

2013-11-05 | E-GEOD-48330 | biostudies-arrayexpress

SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites [array]

Project description:Glucocorticoid receptor (GR) is an essential transcription factor (TF), controlling metabolism, development and immune responses. SUMOylation regulates chromatin occupancy and target gene expression of GR in a locus-selective manner, but the mechanism of regulation has remained elusive. Here, we identify the protein network around chromatin-bound GR by using selective isolation of chromatin-associated proteins and show that the network is affected by receptor SUMOylation, with several nuclear receptor coregulators and chromatin modifiers preferring interaction with SUMOylation-deficient GR and proteins implicated in transcriptional repression preferring interaction with SUMOylation-competent GR. This difference is reflected in our chromatin binding, chromatin accessibility and gene expression data, showing that the SUMOylation-deficient GR is more potent in binding and opening chromatin at glucocorticoid-regulated enhancers and inducing expression of target loci. Blockage of SUMOylation by a SUMO-activating enzyme inhibitor (ML-792) phenocopied to a large extent the consequences of GR SUMOylation deficiency on chromatin binding and target gene expression. Our results thus show that SUMOylation modulates the specificity of GR by regulating its chromatin protein network and accessibility at GR-bound enhancers. We speculate that many other SUMOylated TFs utilize a similar regulatory mechanism.

2021-01-08 | GSE64372 | GEO

SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites [sequencing]

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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

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 chromatin protein network and accessibility at glucocorticoid receptor-binding sites

Project description:Glucocorticoid receptor (GR) is an essential transcription factor (TF), controlling metabolism, development and immune responses. SUMOylation regulates chromatin occupancy and target gene expression of GR in a locus-selective manner, but the mechanism of regulation has remained elusive. Here, we show using selective isolation of chromatin-associated proteins that the protein network around chromatin-bound GR is affected by SUMOylation, with several nuclear receptor coregulators and chromatin modifiers being more avidly associated with SUMOylation-deficient than SUMOylation competent GR. This difference is reflected in our chromatin accessibility and gene expression data, showing that the SUMOylation-deficient GR is more potent in opening chromatin at glucocorticoid-regulated enhancers and inducing expression of their target loci. Our results thus show that SUMOylation determines GR specificity by regulating the chromatin protein network and accessibility at GR-driven enhancers. We speculate that a similar mechanism is utilized by many other SUMOylated TFs.

2021-09-08 | PXD015183 | Pride

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

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