Drug repositioning of inflammatory bowel disease based on co-target gene expression signature of glucocorticoid receptor and TET2
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1051963 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27197225_1.fastq.gz | Fastqsanger.gz | |||
| SRR27197225_2.fastq.gz | Fastqsanger.gz | |||
| SRR27197226_1.fastq.gz | Fastqsanger.gz | |||
| SRR27197226_2.fastq.gz | Fastqsanger.gz | |||
| SRR27197227_1.fastq.gz | Fastqsanger.gz |
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Project description:The glucocorticoid receptor (GR) and ten-eleven translocation 2 (TET2) respectively play a crucial role in regulating immunity and inflammation, and GR interacts with TET2. However, their syn-ergetic roles in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), remain unclear. This study aimed to investigate the co-target gene signatures of GR and TET2 in IBD and provide potential therapeutic interventions for IBD. By integrating public data, we identified 179 GR- and TET2-targeted differentially expressed genes (DEGs) in CD and 401 in UC. These genes were closely associated with immunometabolism, inflammatory responses, and cell stress pathways. In vitro inflammatory cellular models were constructed using LPS-treated HT29 and HCT116 cells, respectively. Drug repositioning based on the co-target gene signatures of GR and TET2 derived from transcriptomic data of UC, CD, and the in vitro model were performed using the Connectivity Map (CMap). BMS-536924 emerged as a top therapeutic candidate, and its validation experiment within the in vitro inflammatory model confirmed its ef-ficacy in mitigating the LPS-induced inflammatory response. This study sheds light on the path-ogenesis of IBD from a new perspective and may accelerate the development of novel therapeutic agents for inflammatory diseases including IBD.
2023-12-18 | GSE250063 | GEO
Project description:The glucocorticoid receptor (GR) and ten-eleven translocation 2 (TET2), respectively, play a crucial role in regulating immunity and inflammation, and GR interacts with TET2. However, their synergetic roles in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), remain unclear. This study aimed to investigate the co-target gene signatures of GR and TET2 in IBD and provide potential therapeutic interventions for IBD. By integrating public data, we identified 179 GR- and TET2-targeted differentially expressed genes (DEGs) in CD and 401 in UC. These genes were found to be closely associated with immunometabolism, inflammatory responses, and cell stress pathways. In vitro inflammatory cellular models were constructed using LPS-treated HT29 and HCT116 cells, respectively. Drug repositioning based on the co-target gene signatures of GR and TET2 derived from transcriptomic data of UC, CD, and the in vitro model was performed using the Connectivity Map (CMap). BMS-536924 emerged as a top therapeutic candidate, and its validation experiment within the in vitro inflammatory model confirmed its efficacy in mitigating the LPS-induced inflammatory response. This study sheds light on the pathogenesis of IBD from a new perspective and may accelerate the development of novel therapeutic agents for inflammatory diseases including IBD.
| S-EPMC10886832 | biostudies-literature
Project description:Background Glucocorticoids (GCs), commonly used for anti-inflammatory and cancer treatments, have been linked to the promotion of cancer metastasis. Yet, the molecular mechanisms behind this potential remain poorly understood. Clarifying these mechanisms is crucial for a nuanced understanding and potential refinement of GC therapies in the context of cancer treatment. Methods In HEK293T cells, co-immunoprecipitation (Co-IP) and chromatin immunoprecipation sequencing (ChIP-seq) were used with antibodies of GR and TET family proteins (TET1, TET2, TET3). Drup repositioning was performed through the LINCS database, using common genes of GR and TET2 in HEK293 and HCT116 cell lines with CRC differentially expressed genes (DEGs). Cell migration and invasion were tested in colorectal cancer (CRC) cell lines with varying glucocorticoid receptor (GR) expression, i.e., HCT116 and HT29 cell lines. Findings Dexamethasone (Dex) treatment resulted in a significant difference in cell migration rates in two CRC cell lines with disparate GR expression levels. Co-IP and ChIP-seq analyses substantiated the interaction between GR and TET family proteins in HEK293T cells. Belinostat, the selected compound, was successfully validated for its potential to counteract the effects of GC-induced inversion in CRC cells in vitro. Transcriptomic analyses of Belinostat-treated HCT116 cells revealed down-regulation of target genes associated with cancer metastasis.. Interpretation This study provides valuable insights into the molecular mechanisms underlying GC-induced metastasis, introducing newly repositioned compounds that could serve as potential adjuvant therapy to GC treatment. Furthermore, it opens avenues for exploring novel drug candidates for CRC treatment.
2024-06-01 | GSE261016 | GEO
Project description:Background Glucocorticoids (GCs), commonly used for anti-inflammatory and cancer treatments, have been linked to the promotion of cancer metastasis. Yet, the molecular mechanisms behind this potential remain poorly understood. Clarifying these mechanisms is crucial for a nuanced understanding and potential refinement of GC therapies in the context of cancer treatment. Methods In HEK293T cells, co-immunoprecipitation (Co-IP) and chromatin immunoprecipation sequencing (ChIP-seq) were used with antibodies of GR and TET family proteins (TET1, TET2, TET3). Drup repositioning was performed through the LINCS database, using common genes of GR and TET2 in HEK293 and HCT116 cell lines with CRC differentially expressed genes (DEGs). Cell migration and invasion were tested in colorectal cancer (CRC) cell lines with varying glucocorticoid receptor (GR) expression, i.e., HCT116 and HT29 cell lines. Findings Dexamethasone (Dex) treatment resulted in a significant difference in cell migration rates in two CRC cell lines with disparate GR expression levels. Co-IP and ChIP-seq analyses substantiated the interaction between GR and TET family proteins in HEK293T cells. Belinostat, the selected compound, was successfully validated for its potential to counteract the effects of GC-induced inversion in CRC cells in vitro. Transcriptomic analyses of Belinostat-treated HCT116 cells revealed down-regulation of target genes associated with cancer metastasis.. Interpretation This study provides valuable insights into the molecular mechanisms underlying GC-induced metastasis, introducing newly repositioned compounds that could serve as potential adjuvant therapy to GC treatment. Furthermore, it opens avenues for exploring novel drug candidates for CRC treatment.
2024-06-01 | GSE256159 | GEO
Project description:Glucocorticoid promotes metastasis of colorectal cancer via co-regulation of glucocorticoid receptor and TET2 (ChIP-Seq)
| PRJNA1084827 | ENA
Project description:Glucocorticoid promotes metastasis of colorectal cancer via co-regulation of glucocorticoid receptor and TET2 (RNA-Seq)
| PRJNA1078347 | ENA
Project description:Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes implicated in cancer and in aging due to its role as a global epigenetic modifier. TET2 has a large N-terminal domain followed by a catalytic C-terminal. Previous reports have demonstrated that the catalytic domain remains active independent of the N-terminal domain. As such, the function of the N-terminus of this large protein remains poorly characterized. Here, we identify that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3s bind TET2 when phosphorylated at serine 99 (S99). AMPK-mediated phosphorylation at S99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine. 14-3-3s’ interaction with TET2 serves to protect S99 phosphorylation. Disruption of this interaction leads to both reduced TET2 phosphorylation and decreased protein stability. Furthermore, we identify that the protein phosphatase 2A (PP2A) can interact with TET2 and dephosphorylates S99. Collectively, our study provides novel insights into the role of the N-terminal domain in TET2 regulation. Moreover, they demonstrate the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels and/or activity.
2020-01-13 | PXD016160 | Pride
Project description:Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT MN, clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.
2020-09-09 | PXD020550 | Pride
Project description:We performed RNA-seq on peripheral blood mononuclear cells (PBMC) from healthy human donors treated with interferon alpha 2a (1000IU/mL) +/- dexamethasone 10^-7M, with the aims of studying interactions between IFN and glucocorticoid induced gene expression, as well as identifying potential transcripts that may be used as a glucocorticoid exposure signature in clinical practice in patients with SLE. Transcripts identified from RNA-seq data were analysed in SLE patient data sets to validate clinical utility. We found that dexamethasone minimally impacts on interferon stimulated gene expression however IFN altered gene transcription of many previously reported glucocorticoid induced genes.
2021-03-31 | GSE159094 | GEO
Project description:Genome wide DNA methylation profiling of patient samples with TET2 mutations and Wild type TET2 status . The Illumina Infinium HumanMethylation 450_15017482_v.1.1 was used to obtain DNA methylation profiles across approximately 482,421 CpGs in fresh frozen lymphoma samples. Samples include 19 TET2 wild type and 12 TET2 mutant samples. Bisulphite converted DNA from the 31 samples were hybridised to the Illumina Infinium HM450K Human Methylation Beadchip v1.2
2013-10-10 | E-GEOD-37362 | biostudies-arrayexpress