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SOCS1 regulates a subset of NFκB-target genes through direct chromatin binding and defines macrophage functional phenotypes (ChIP-Seq).

ABSTRACT: Suppressor of cytokine signaling-1 (SOCS1) exerts control over inflammation by targeting p65 NFκB for degradation in addition to its canonical role regulating cytokine signaling. We report here that SOCS1 does not operate on all p65 targets equally, instead localizing to a select subset of pro-inflammatory genes. Promoter-specific interactions of SOCS1 and p65 determine the subset of genes activated by NFκB during systemic inflammation, with profound consequences for cytokine responses, immune cell mobilization, and tissue injury. Nitric oxide synthase-1 (NOS1)-derived NO is required and sufficient for displacement of SOCS1 from chromatin, permitting full transcriptional activation of these genes. Single cell transcriptomic analysis of NOS1-deficient animals led to the detection of a regulatory macrophage subset, which exerts potent suppression on inflammatory cytokine responses and tissue remodeling. These results provide the first example of a redox-sensitive, gene-specific mechanism for converting macrophages from cells that regulate inflammation to cells licensed to promote aggressive and potentially injurious inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE225833 | GEO | 2023/03/01

REPOSITORIES: GEO

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SOCS1 regulates a subset of NFκB-target genes through direct chromatin binding and defines macrophage functional phenotypes (RNA-Seq).

Project description:Suppressor of cytokine signaling-1 (SOCS1) exerts control over inflammation by targeting p65 NFκB for degradation in addition to its canonical role regulating cytokine signaling. We report here that SOCS1 does not operate on all p65 targets equally, instead localizing to a select subset of pro-inflammatory genes. Promoter-specific interactions of SOCS1 and p65 determine the subset of genes activated by NFκB during systemic inflammation, with profound consequences for cytokine responses, immune cell mobilization, and tissue injury. Nitric oxide synthase-1 (NOS1)-derived NO is required and sufficient for displacement of SOCS1 from chromatin, permitting full transcriptional activation of these genes. Single cell transcriptomic analysis of NOS1-deficient animals led to the detection of a regulatory macrophage subset, which exerts potent suppression on inflammatory cytokine responses and tissue remodeling. These results provide the first example of a redox-sensitive, gene-specific mechanism for converting macrophages from cells that regulate inflammation to cells licensed to promote aggressive and potentially injurious inflammation.

2023-03-01 | GSE225831 | GEO

SOCS1 regulates a subset of NFκB-target genes through direct chromatin binding and defines macrophage functional phenotypes (scRNA-Seq).

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SILAC-based quantitative proteomics implicates SOCS1 in modulating protein constituents of large macromolecular complexes in hepatocytes

Project description:Suppressor of Cytokine Signaling 1 (SOCS1) functions as a tumor suppressor in hepatocellular carcinoma by regulating cytokine, growth factor and other signaling pathways. The tumor suppressor functions of SOCS1 are mediated partly via promoting ubiquitination and proteasomal degradation of several signaling proteins. In this study, we used an unbiased approach to characterize SOCS1-mediated changes in the protein profile of hepatocytes. The murine HCC cell line Hepa1-6 transduced with wildtype SOCS1, an SH2 domain mutant or the empty lentiviral vector were grown in Stable Isotopic Labelling of Amino acids in Cell culture (SILAC) media. The cells were stimulated with hepatocyte growth factor or left at steady state. Following cell lysis, proteins were separated on SDS-PAGE gels and peptides extracted by in-gel trypsinization were analyzed by mass spectrometry. Differentially modulated proteins identified and quantified were subjected to pathway enrichment analysis. In total, 3440 proteins were identified in Hepa cells in the presence of SOCS1 at steady state, of which 181 proteins were significantly modulated by SOCS1. The SH2 domain mutation and HGF stimulation increased the number of differentially modulated proteins, which showed only a limited overlap with SOCS1-modulated proteins. Protein interaction network analysis revealed enrichment of SOCS1-modulated proteins within multiprotein complexes such as ubiquitin conjugating enzymes, proteasome, mRNA spliceosome, mRNA exosome and mitochondrial ribosome. Further analysis indicated SOCS1-dependent regulation of the UBE2D ubiquitin conjugating enzymes, which are implicated in growth factor receptor signaling, indirectly via an unknown protein. Given the ubiquitous and highly regulated induction of SOCS1 by diverse cellular stimuli, our findings suggest a fundamental role of SOCS1 in regulating large macromolecular complexes that are important for cellular homeostasis.

2021-02-01 | PXD019135 | Pride

Interferon-gamma timecourse in IFNg-/- and SOCS1-/-IFNg-/- mouse livers

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The tumor suppressor SOCS1 diminishes tolerance to oxidative stress in hepatocellular carcinoma

Project description:SOCS1 is a tumor suppressor in hepatocellular carcinoma. Recently we showed that loss of SOCS1 in hepatocytes promotes NRF2 activation. Here we investigated how SOCS1 expression affected oxidative stress response in HCC cells. Murine Hepa1-6 cells expressing SOCS1 (Hepa-SOCS1) or control vector (Hepa-Vector) were treated with cisplatin or tert-butyl hydroperoxide (t-BHP). Induction of NRF2 and its target genes, oxidative stress, lipid peroxidation, cell survival and cellular proteome profiles were evaluated. NRF2 induction was significantly reduced in Hepa-SOCS1 cells. The gene and protein expression of NRF2 targets were differentially induced in Hepa-Vector cells but markedly suppressed in Hepa-SOCS1 cells. Hepa-SOCS1 cells displayed increased induction of reactive oxygen species (ROS) but reduced lipid peroxidation. Nonetheless, Hepa-SOCS1 cells treated with cisplatin or t-BHP showed reduced survival. GCLC, poorly induced in Hepa-SOCS1 cells, showed a strong positive correlation with NFE2L2 and an inverse correlation with SOCS1 in the TCGA-LIHC transcriptomic data. Proteomic analysis of Hepa-Vector and Hepa-SOCS1 cells revealed that SOCS1 differentially modulated many proteins involved in diverse molecular pathways including those implicated in mitochondrial ROS generation and detoxification by peroxiredoxin and thioredoxin systems. Our findings indicate that maintaining sensitivity to oxidative stress is an important tumor suppression mechanism of SOCS1 in HCC.

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Rational design of a SOCS1-edited tumor infiltrating lymphocyte therapy for solid tumors using CRISPR/Cas9 screens [IVP27_B16Ova]

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