Influence of SUMOylation on chromatin structure in hIPSCs (ChiPS4) assessed by time-resolved ATAC-seq in response to ML792 treatment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Marek Gierlinski
PROVIDER: E-MTAB-9961 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:SUMOylation is thought to regulate chromatin structure and accessibility thus affecting gene expression. In order to assess these potential roles of SUMOylation in human pluripotent stem cells, ChiPS4 cells were treated with ML792 (selective SUMO E1 inhibitor) or DMSO (vehicle control) for the following times: 4, 8, 24 and 48h. At each time point samples were collected for western blotting (control for the efficacy of treatment), RNA-seq (total RNA extracted using RNeasy Mini Kit, samples in 4 replicates per time point) and ATAC-seq (using Omni-ATAC protocol). Samples were further used for library preparation and sequenced using the Illumina NovaSeq 6000 S4.
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Project description:SUMOylation, a posttranslational modification, regulates proteins by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins. Here we use TAK-981, a selective SUMO-activating enzyme (SAE) inhibitor, to inhibit global SUMOylation in glucocorticoid sensitive and resistant multiple myeloma cell lines.
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Project description:SUMOylation, a post-translational protein modification, is dramatically upregulated and critically involved in heat stress response conservatively among species. Previous studies in Arabidopsis indicated that numerous chromatin associated proteins are SUMOylation substrates and most of heat-enhancing SUMOylation reactions occur in nucleus. However, the global functional connection between gene expression regulation and SUMOylation on chromatin is completely unknown in plant cells. Here we show a genome-wide relationship of chromatin-associated SUMOylation and transcription switches under room temperature, heat stress, and recovering conditions in Arabidopsis. The SUMO-associated chromatin sites, characterized via whole-genome ChIP-seq assays, are generally correlated with active chromatin markers. In response to heat stress, we found chromatin-associated SUMO signals increased at promoter-transcriptional start site regions and decreased in the gene bodies. Further RNA-seq analysis supported the role of chromatin-associated SUMOylation in activation of transcription during rapid responses to high temperature. Changing of SUMO signals on chromatin is correlated with upregulation of heat-responsive genes and downregulation of growth-related genes. Disruption of the SUMO ligase gene SIZ1 abolishes SUMO signals on chromatin and attenuates the rapid transcriptional responses to heat stress. Interestingly, the SUMO signal peaks are enriched in DNA elements recognized by distinguished groups of transcription factors under different temperature conditions. Collectively, our data provide evidence that SUMOylation on chromatin regulates transcription switches during development and heat stress response, improving our understanding on the precise roles of SUMOylation in plant cells.
2020-08-04 | GSE140506 | GEO
Project description:SUMOylation, a post-translational protein modification, is dramatically upregulated and critically involved in heat stress response conservatively among species. Previous studies in Arabidopsis indicated that numerous chromatin associated proteins are SUMOylation substrates and most of heat-enhancing SUMOylation reactions occur in nucleus. However, the global functional connection between gene expression regulation and SUMOylation on chromatin is completely unknown in plant cells. Here we show a genome-wide relationship of chromatin-associated SUMOylation and transcription switches under room temperature, heat stress, and recovering conditions in Arabidopsis. The SUMO-associated chromatin sites, characterized via whole-genome ChIP-seq assays, are generally correlated with active chromatin markers. In response to heat stress, we found chromatin-associated SUMO signals increased at promoter-transcriptional start site regions and decreased in the gene bodies. Further RNA-seq analysis supported the role of chromatin-associated SUMOylation in activation of transcription during rapid responses to high temperature. Changing of SUMO signals on chromatin is correlated with upregulation of heat-responsive genes and downregulation of growth-related genes. Disruption of the SUMO ligase gene SIZ1 abolishes SUMO signals on chromatin and attenuates the rapid transcriptional responses to heat stress. Interestingly, the SUMO signal peaks are enriched in DNA elements recognized by distinguished groups of transcription factors under different temperature conditions. Collectively, our data provide evidence that SUMOylation on chromatin regulates transcription switches during development and heat stress response, improving our understanding on the precise roles of SUMOylation in plant cells.
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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
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Project description:Genome wide localization of SUMO1 and SUMO2/3 proteins revealed an asscociation of SUMO proetins with active chromatin. SUMO proteins are enriched at super enhancers and enhancers and SUMOylation regulates a subset of these super enhancers. Super enhancers regulated by SUMOylation were enriched for transcription factor TFAP2C and SUMOylation negatively regulates TFAP2C localization to enhancers and super enhancers. Proteomics and ChIP-PCR at MYC SE suggests that chromatin bound TFAP2C recruits histone deacetylation complexes that increases upon SAE2 knockdown. Conversely, SUMOylation promoted TFAP2C asscociation with pre-mRNA splicing machinery components. Taken together, our study revealed a critical role of SUMOylation in chromatin modification through an AP-2 family of transcription factor, TFAP2C and a potential role of TFAP2C in pre-mRNA splicing.
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Project description:Genome wide localization of SUMO1 and SUMO2/3 proteins revealed an asscociation of SUMO proetins with active chromatin. SUMO proteins are enriched at super enhancers and enhancers and SUMOylation regulates a subset of these super enhancers. Super enhancers regulated by SUMOylation were enriched for transcription factor TFAP2C and SUMOylation negatively regulates TFAP2C localization to enhancers and super enhancers. Proteomics and ChIP-PCR at MYC SE suggests that chromatin bound TFAP2C recruits histone deacetylation complexes that increases upon SAE2 knockdown. Conversely, SUMOylation promoted TFAP2C asscociation with pre-mRNA splicing machinery components. Taken together, our study revealed a critical role of SUMOylation in chromatin modification through an AP-2 family of transcription factor, TFAP2C and a potential role of TFAP2C in pre-mRNA splicing.
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Project description:Post-translational modification with SUMO is known to regulate the activity of transcription factors, but how SUMOylation of individual proteins might influence immunity is mostly unexplored. The NFAT transcription factors play an essential role in antigen receptor-mediated gene regulation. SUMOylation of NFATc1 represses IL-2 in vitro, but its role in T cell-mediated immune responses in vivo is not clear. To this end, we generated a novel Nfatc1 transgenic mouse, which prevents SUMO modification of NFATc1. Avoidance of NFATc1 SUMOylation ameliorated experimental autoimmune encephalomyelitis as well as graft-versus-host disease. An elevated IL-2 production promoted Treg expansion and suppressed autoreactive or alloreactive T cells. Mechanistically, increased IL-2 secretion counteracted IL-17 and IFN-γ expression through STAT5 and Blimp-1 induction. Then, Blimp-1 repressed IL-2 itself and the as well induced, proliferation-associated survival factor Bcl2A1. Collectively, we demonstrate that prevention of NFATc1 SUMOylation fine-tunes T-cell responses towards lasting tolerance. Thus, targeting NFATc1 SUMOylation presents a novel and promising strategy to treat T cell-mediated inflammatory diseases.
2020-07-01 | GSE148087 | GEO
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
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Project description:Post-translational modification with SUMO is known to regulate the activity of transcription factors, but how SUMOylation of individual proteins might influence immunity is mostly unexplored. NFATc1 is a transcription factor of the family of ‘Nuclear Factors of Activated T-cells’ which plays an essential role in antigen receptor-mediated gene regulation. It is expressed in multiple isoforms of which the longer isoforms can be modified by SUMOylation. SUMO modification of NFATc1 represses IL-2 in vitro, but its role in T cell-mediated immune responses in vivo is not clear. To this end, we generated a novel Nfatc1 transgenic mouse with lysine to arginine mutations, which abolish the SUMO modification within NFATc1’s C-terminal domain. Inhibition of NFATc1 SUMOylation ameliorated experimental autoimmune encephalomyelitis as well as graft-versus-host disease. This was due to elevated IL-2 production that promoted Treg expansion and suppressed autoreactive or alloreactive T cells. Mechanistically, increased IL-2 secretion counteracted IL-17 and IFN-γ expression through STAT5 and Blimp-1 induction. Blimp-1 also repressed IL-2 itself and the as well induced survival factor Bcl2A1. Still, lack of NFATc1 sumoylation fine-tunes T-cell responses towards lasting tolerance implying a novel approach to treat inflammatory diseases.
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