SUMOylation inhibition potentiates the glucocorticoid receptor to program growth arrest of acute lymphoblastic leukemia cells
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PROVIDER: PRJNA976648 | ENA |
REPOSITORIES: ENA
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Project description:SUMOylation inhibition potentiates the glucocorticoid receptor to program growth arrest of acute lymphoblastic leukemia cells (ChIP-seq)
| PRJNA976650 | ENA
Project description:SUMOylation inhibition potentiates the glucocorticoid receptor to program growth arrest of acute lymphoblastic leukemia cells (RNA-seq)
| PRJNA976653 | ENA
Project description:SUMOylation inhibition potentiates the glucocorticoid receptor to program growth arrest of acute lymphoblastic leukemia cells (ATAC-seq)
| PRJNA976651 | ENA
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.
2025-01-20 | GSE233552 | GEO
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.
2025-01-20 | GSE233551 | GEO
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.
2025-01-20 | GSE233550 | GEO
Project description:Purpose of these experiments was to assess the effect of glucocorticoid receptor SUMOylation on its protein-protein interactions using BioID. Experiments were performed with SUMOylation deficient GR3KR (K277,293,703R) fused to the BirA* biotin ligase tag.
2021-01-11 | PXD017713 | Pride
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: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