STAT3 controls IL-6-induced epigenomic remodeling and restrains a latent STAT1-associated interferon program in human macrophages
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE348676 | GEO | 2026/09/28
REPOSITORIES: GEO
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Project description:Interleukin-6 (IL-6) is a pleiotropic cytokine that drives macrophage functions ranging from tissue homeostasis to inflammation, yet how STAT3 specifies these divergent outcomes remains unclear. By integrating transcriptomic and epigenomic profiling with selective STAT3 degradation, we show that STAT3 controls IL-6-induced epigenomic remodeling and restrains a latent STAT1-associated interferon program in human macrophages. Graded STAT3 chromatin recruitment scales with locus-specific H3K27ac deposition and transcriptional output across homeostatic and inflammatory programs. STAT3 degradation permits STAT1 recruitment at a subset of regulatory regions and engages a delayed amplification loop that is partially dependent on STING and type I IFN signaling. In severe COVID-19, monocytes exhibit exaggerated STAT3-associated inflammatory signatures together with attenuated STAT1-associated interferon responses, consistent with a skewed STAT3–STAT1 balance. These findings define a framework in which STAT3 calibrates IL-6-induced chromatin output while maintaining pathway fidelity by limiting STAT1 crosstalk.
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Project description:Interleukin-6 (IL-6) is a pleiotropic cytokine that drives macrophage functions ranging from tissue homeostasis to inflammation, yet how STAT3 specifies these divergent outcomes remains unclear. By integrating transcriptomic and epigenomic profiling with selective STAT3 degradation, we show that STAT3 controls IL-6-induced epigenomic remodeling and restrains a latent STAT1-associated interferon program in human macrophages. Graded STAT3 chromatin recruitment scales with locus-specific H3K27ac deposition and transcriptional output across homeostatic and inflammatory programs. STAT3 degradation permits STAT1 recruitment at a subset of regulatory regions and engages a delayed amplification loop that is partially dependent on STING and type I IFN signaling. In severe COVID-19, monocytes exhibit exaggerated STAT3-associated inflammatory signatures together with attenuated STAT1-associated interferon responses, consistent with a skewed STAT3–STAT1 balance. These findings define a framework in which STAT3 calibrates IL-6-induced chromatin output while maintaining pathway fidelity by limiting STAT1 crosstalk.
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Project description:Interleukin-6 (IL-6) is a pleiotropic cytokine that drives macrophage functions ranging from tissue homeostasis to inflammation, yet how STAT3 specifies these divergent outcomes remains unclear. By integrating transcriptomic and epigenomic profiling with selective STAT3 degradation, we show that STAT3 controls IL-6-induced epigenomic remodeling and restrains a latent STAT1-associated interferon program in human macrophages. Graded STAT3 chromatin recruitment scales with locus-specific H3K27ac deposition and transcriptional output across homeostatic and inflammatory programs. STAT3 degradation permits STAT1 recruitment at a subset of regulatory regions and engages a delayed amplification loop that is partially dependent on STING and type I IFN signaling. In severe COVID-19, monocytes exhibit exaggerated STAT3-associated inflammatory signatures together with attenuated STAT1-associated interferon responses, consistent with a skewed STAT3–STAT1 balance. These findings define a framework in which STAT3 calibrates IL-6-induced chromatin output while maintaining pathway fidelity by limiting STAT1 crosstalk.
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Project description:Interleukin-6 (IL-6) is a pleiotropic cytokine that drives macrophage functions ranging from tissue homeostasis to inflammation, yet how STAT3 specifies these divergent outcomes remains unclear. By integrating transcriptomic and epigenomic profiling with selective STAT3 degradation, we show that STAT3 controls IL-6-induced epigenomic remodeling and restrains a latent STAT1-associated interferon program in human macrophages. Graded STAT3 chromatin recruitment scales with locus-specific H3K27ac deposition and transcriptional output across homeostatic and inflammatory programs. STAT3 degradation permits STAT1 recruitment at a subset of regulatory regions and engages a delayed amplification loop that is partially dependent on STING and type I IFN signaling. In severe COVID-19, monocytes exhibit exaggerated STAT3-associated inflammatory signatures together with attenuated STAT1-associated interferon responses, consistent with a skewed STAT3–STAT1 balance. These findings define a framework in which STAT3 calibrates IL-6-induced chromatin output while maintaining pathway fidelity by limiting STAT1 crosstalk.
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Project description:Interleukin-6 (IL-6) is a pleiotropic cytokine that drives macrophage functions ranging from tissue homeostasis to inflammation, yet how STAT3 specifies these divergent outcomes remains unclear. By integrating transcriptomic and epigenomic profiling with selective STAT3 degradation, we show that STAT3 controls IL-6-induced epigenomic remodeling and restrains a latent STAT1-associated interferon program in human macrophages. Graded STAT3 chromatin recruitment scales with locus-specific H3K27ac deposition and transcriptional output across homeostatic and inflammatory programs. STAT3 degradation permits STAT1 recruitment at a subset of regulatory regions and engages a delayed amplification loop that is partially dependent on STING and type I IFN signaling. In severe COVID-19, monocytes exhibit exaggerated STAT3-associated inflammatory signatures together with attenuated STAT1-associated interferon responses, consistent with a skewed STAT3–STAT1 balance. These findings define a framework in which STAT3 calibrates IL-6-induced chromatin output while maintaining pathway fidelity by limiting STAT1 crosstalk.
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Project description:Interleukin-6 (IL-6) is a pleiotropic cytokine that drives macrophage functions ranging from tissue homeostasis to inflammation, yet how STAT3 specifies these divergent outcomes remains unclear. By integrating transcriptomic and epigenomic profiling with selective STAT3 degradation, we show that STAT3 controls IL-6-induced epigenomic remodeling and restrains a latent STAT1-associated interferon program in human macrophages. Graded STAT3 chromatin recruitment scales with locus-specific H3K27ac deposition and transcriptional output across homeostatic and inflammatory programs. STAT3 degradation permits STAT1 recruitment at a subset of regulatory regions and engages a delayed amplification loop that is partially dependent on STING and type I IFN signaling. In severe COVID-19, monocytes exhibit exaggerated STAT3-associated inflammatory signatures together with attenuated STAT1-associated interferon responses, consistent with a skewed STAT3–STAT1 balance. These findings define a framework in which STAT3 calibrates IL-6-induced chromatin output while maintaining pathway fidelity by limiting STAT1 crosstalk.
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Project description:Interleukin-6 (IL-6) is a pleiotropic cytokine that drives macrophage functions ranging from tissue homeostasis to inflammation, yet how STAT3 specifies these divergent outcomes remains unclear. By integrating transcriptomic and epigenomic profiling with selective STAT3 degradation, we show that STAT3 controls IL-6-induced epigenomic remodeling and restrains a latent STAT1-associated interferon program in human macrophages. Graded STAT3 chromatin recruitment scales with locus-specific H3K27ac deposition and transcriptional output across homeostatic and inflammatory programs. STAT3 degradation permits STAT1 recruitment at a subset of regulatory regions and engages a delayed amplification loop that is partially dependent on STING and type I IFN signaling. In severe COVID-19, monocytes exhibit exaggerated STAT3-associated inflammatory signatures together with attenuated STAT1-associated interferon responses, consistent with a skewed STAT3–STAT1 balance. These findings define a framework in which STAT3 calibrates IL-6-induced chromatin output while maintaining pathway fidelity by limiting STAT1 crosstalk.
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Project description:Interleukin-21 (IL-21) is a type 1 cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4+ T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4+ T cells. RNA-Seq analysis of CD4+ T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3, and interestingly, ChIP-Seq analysis showed that STAT3 binding at Tbx21 and Ifng loci was attenuated in Stat1-deficient cells. Moreover, opposing actions of STAT1 and STAT3 on IFN- expression in CD4+ T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis (LCMV) infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4+ T cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES), which is caused by STAT3 deficiency. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions. Genome-wide transcription factors mapping and binding of STAT3 in mouse CD4+ T cells in both WT and Stat1-deficient mice. RNA-Seq is performed in mouse CD4+ T cells in WT, Stat1-deficient and Stat3-deficient mice.
2015-07-01 | E-GEOD-63204 | biostudies-arrayexpress
Project description:Interleukin-21 (IL-21) is a type 1 cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4+ T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4+ T cells. RNA-Seq analysis of CD4+ T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3, and interestingly, ChIP-Seq analysis showed that STAT3 binding at Tbx21 and Ifng loci was attenuated in Stat1-deficient cells. Moreover, opposing actions of STAT1 and STAT3 on IFN- expression in CD4+ T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis (LCMV) infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4+ T cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES), which is caused by STAT3 deficiency. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions.
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Project description:Epithelial ovarian cancer is the 7th most common cancer in women worldwide and is the most fatal of all female reproductive cancers. JAK/STAT signaling is oncogenic in ovarian cancer and has been reported to be constitutively active in a proportion of chemotherapy resistant ovarian cancer cell lines and tumors. However, the precise molecular mechanisms by which STAT1 and STAT3 function in ovarian cancer are not well understood and the consequences of their specific inhibition have yet to be determined. Methods: To delineate the specific functions of STAT1 and STAT3 in high grade serous and endometrioid ovarian cancer cell lines, we treated OVSAHO and MDAH cells with IFNγ or IL6, canonical STAT1 and STAT3 activators respectively, with and without STAT1 or STAT3 specific siRNAs. We conducted RNA-sequencing and ChIP-sequencing following treatment to delineate direct and indirect target genes for STAT1 and STAT3. We generated a STAT1 and STAT3 specific gene signature and applied them to publicly available datasets to test their predictive and prognostic ability. Results: Using these global and unbiased datasets, we identified STAT1 and STAT3 specific pathways, developed STAT1 and STAT3 specific gene signatures, and applied these signatures to publicly available ovarian cancer patient data. We determined the STAT1 and STAT3 signature’s associations with tumor development, chemotherapy responsiveness and long-term patient outcomes. Conclusions: Our studies have further informed the precise mechanisms of STAT1 and STAT3 action in the two most common subtypes of ovarian cancer and have defined gene signatures that are both prognostic and predictive.
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