E-MTAB-10087
Ontology highlight
ABSTRACT:
PROVIDER: E-MTAB-10087 | ExpressionAtlas | 2023-06-15
REPOSITORIES: ExpressionAtlas
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| E-MTAB-10087-analysis-methods.tsv | Tabular | |||
| E-MTAB-10087-analytics.tsv | Tabular | |||
| E-MTAB-10087-atlasExperimentSummary.Rdata | Rdata | |||
| E-MTAB-10087-configuration.xml | Xml | |||
| E-MTAB-10087-g4_g1-mvaPlot.png | Other |
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Project description:RNA-seq: STAT1 and STAT3 transcription factors sense and interpret changes in inflammation through engagement of specific enhancers
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Project description:Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. We previously described a CD44+CD24-pSTAT3+ cancer cell subpopulation with stem cell-like features in breast cancer that is dependent on JAK/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell-type in IBC and are commonly pSTAT3+. Combination of JAK/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. We developed and characterized IBC cell lines resistant to paclitaxel and doxorubicin to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed genes associated with lineage identity and inflammation were enriched in chemotherapy resistant derivatives. Integrated pSTAT3 ChIP-seq and RNA-seq analyses showed pSTAT3 regulates genes related to inflammation and epithelial to mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. We also investigated cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq. We identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare pre-existing subpopulations or an acquired change. Lastly, we showed that combination treatment with paclitaxel and JAK/STAT3 inhibition prevented the emergence of this more mesenchymal chemo-resistant subpopulation. Our results provide mechanistic rational for combination of chemotherapy with inhibition of JAK/STAT3 signaling as a new more effective therapeutic strategy in IBC.
2022-11-04 | MSV000090647 | MassIVE
Project description:Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. We previously described a CD44+CD24-pSTAT3+ cancer cell subpopulation with stem cell-like features in breast cancer that is dependent on JAK/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell-type in IBC and are commonly pSTAT3+. Combination of JAK/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. We developed and characterized IBC cell lines resistant to paclitaxel and doxorubicin to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed genes associated with lineage identity and inflammation were enriched in chemotherapy resistant derivatives. Integrated pSTAT3 ChIP-seq and RNA-seq analyses showed pSTAT3 regulates genes related to inflammation and epithelial to mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. We also investigated cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq. We identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare pre-existing subpopulations or an acquired change. Lastly, we showed that combination treatment with paclitaxel and JAK/STAT3 inhibition prevented the emergence of this more mesenchymal chemo-resistant subpopulation. Our results provide mechanistic rational for combination of chemotherapy with inhibition of JAK/STAT3 signaling as a new more effective therapeutic strategy in IBC.
2022-11-04 | MSV000090647 | GNPS
Project description:STAT3, an essential transcription factor with pleiotropic functions, plays critical roles in the pathogenesis of autoimmunity. Despite recent data linking STAT3 with inflammatory bowel disease, exactly how it contributes to chronic intestinal inflammation is not known. Using a T cell transfer model of colitis we found that STAT3 expression in T cells was essential for the induction of both colitis and systemic inflammation. STAT3 was critical in modulating the balance of T helper 17 (Th17) and regulatory T (Treg) cells, as well as in promoting CD4+ T cell proliferation. We used chromatin immunoprecipitation and massive parallel sequencing (ChIP-Seq) to define the genome-wide targets of STAT3 in CD4+ T cells. We found that STAT3 bound to multiple genes involved in Th17 cell differentiation, cell activation, proliferation and survival, regulating both expression and epigenetic modifications. Thus, STAT3 orchestrates multiple critical aspects of T cell function in inflammation and homeostasis. This SuperSeries is composed of the following subset Series: GSE21669: Diverse Targets of the Transcription Factor STAT3 Contribute to T Cell Pathogenicity and Homeostasis [ChIP-seq] GSE21670: Diverse Targets of the Transcription Factor STAT3 Contribute to T Cell Pathogenicity and Homeostasis [Affymetrix Expression] Refer to individual Series
2010-05-29 | E-GEOD-21671 | biostudies-arrayexpress
Project description:Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NFκB, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-γ (a STAT1 activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NFκB transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NFκB and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NFκB, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging. Biological triplicate experiments were performed for each cytokine treatment condition or control treatment.
2015-07-01 | E-GEOD-68940 | biostudies-arrayexpress
Project description:Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NFκB, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-γ (a STAT1 activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NFκB transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NFκB and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NFκB, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging. Biological triplicate experiments were performed for each cytokine treatment condition or control treatment.
2015-07-01 | E-GEOD-68941 | biostudies-arrayexpress
Project description:Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NFκB, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-γ (a STAT1 activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NFκB transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NFκB and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NFκB, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging. Biological duplicate or triplicate experiments were profiled for each cytokine treatment or control condition
2015-07-01 | E-GEOD-68942 | biostudies-arrayexpress
Project description:The cytokines interleukin 1β and 6 (IL-1β, IL-6) mediate the systemic acute and chronic inflammatory response. In liver, they both regulate the secretion of acute-phase proteins which curb infection and tissue damage. Using RNA-seq, we show that these cytokines regulate gene transcription in a multifaceted manner to modulate gene expression, leading both to synergistic and antagonistic expression patterns. By mapping changes in enhancer landscape and transcription factor occupancy following cytokine treatment, we show that synergistic gene expression was achieved by cooperation between cytokine-induced transcription factors on the chromatin template. At a subset of enhancers proximal to synergistically-induced acute-phase genes, IL-1β led to enhancer priming and an increase in STAT3 binding. These effects were mediated by NF-κB and were enhancer-specific rather that influencing the entirety of STAT3 binding. Our findings reveal that STAT3-NF-κB crosstalk at the chromatin template plays a major role in transcriptional regulation during inflammation
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