JAK-STAT signaling maintains homeostasis in T cells and macrophages (spatial transcriptomics)
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ABSTRACT:
PROVIDER: PRJNA943499 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23821929.fastq.gz | Fastqsanger.gz | |||
| SRR23821930.fastq.gz | Fastqsanger.gz | |||
| SRR23821931.fastq.gz | Fastqsanger.gz | |||
| SRR23821932.fastq.gz | Fastqsanger.gz | |||
| SRR23821933.fastq.gz | Fastqsanger.gz |
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Project description:Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice – but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse transcription-regulatory programs, including gene regulation by STAT2 and IRF9 independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wildtype mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcription-regulatory state and helps prepare these cells for rapid response to immune stimuli.
2024-02-24 | GSE227168 | GEO
Project description:JAK-STAT signaling maintains homeostasis in T cells and macrophages
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Project description:Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice – but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse transcription-regulatory programs, including gene regulation by STAT2 and IRF9 independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wildtype mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcription-regulatory state and helps prepare these cells for rapid response to immune stimuli.
2024-02-24 | GSE204735 | GEO
Project description:JAK-STAT signaling maintains homeostasis in T cells and macrophages (RNA-seq)
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Project description:Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice – but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse transcription-regulatory programs, including gene regulation by STAT2 and IRF9 independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wildtype mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcription-regulatory state and helps prepare these cells for rapid response to immune stimuli.
2024-02-24 | GSE204734 | GEO
Project description:JAK-STAT pathways maintain homeostasis in immune cells (ATAC-Seq)
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Project description:The JAK/STAT pathway is an essential signalling cascade required for multiple processes during both development and for adult homeostasis. A key question in understanding this pathway is how it is regulated in different cell contexts. Here we have examined how endocytic processing contributes to signalling by the single cytokine receptor, Domeless, in Drosophila melanogaster cells. We identify an evolutionarily conserved di-Leu motif that is required for Domeless internalisation and show that endocytosis is required for activation of a subset of Domeless targets. Our data indicate that endocytosis both qualitatively and quantitatively regulates Domeless signalling. STAT92E, the single STAT transcription factor in Drosophila, appears to be the target of endocytic regulation and our studies show that phosphorylation of STAT92E on Tyr704, while necessary, is not always sufficient for target transcription. Finally, we identify a conserved residue, Thr702, which is essential for Tyr704 phosphorylation. Taken together, our findings identify previously unknown aspects of JAK/STAT pathway regulation likely to play key roles in the spatial and temporal regulation of signalling in vivo.
2020-09-29 | PXD020719 | Pride
Project description:Toxic epidermal necrolysis (TEN) is a fatal cutaneous adverse drug reaction and an emerging public health issue 1-3. Triggered by common medications, patients suffer from fulminant epidermal detachment and long-term sequalae. Although molecular mechanisms driving keratinocyte cytotoxicity have been reported, no effective therapy exists4-6. In recent years, powerful omics technologies have expanded into spatial context and we reasoned that single cell spatial proteomics could uncover novel therapeutic targets in TEN. Applying Deep Visual Proteomics7,8 to formalin fixed paraffin embedded archived skin-tissue biopsies of three types of cutaneous drug reactions with varying severity quantified over 5,000 proteins in keratinocytes and skin-infiltrating immune cells. Most strikingly, this revealed a robust enrichment of Type-I- and -II interferon signature in the immune cell and keratinocyte compartment of TEN patients, along with a drastic activation of pSTAT1. Targeted inhibition with pan-JAK inhibitor (JAKi) Tofacitinib reduced keratinocyte-directed cytotoxicity in a novel live-cell imaging assay, using patient-derived keratinocytes and PBMCs. Furthermore, oral administration of pan-JAKi Tofacitinib or Baricitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. This study uncovers the JAK-STAT and interferon signaling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAK inhibition as a curative therapy.
2025-01-13 | PXD044477 | Pride
Project description:Purpose: analyze ligand and receptor genes regulated at early time points following JAK STAT pathway stimulation During development and homeostasis, cells integrate multiple signals originating either from neighboring cells or systemically. In turn, responding cells can produce signals that act in an autocrine, paracrine, or endocrine manner. Although the nature of the signals and pathways used in cell-cell communication are well characterized, we lack, in most cases, an integrative view of signaling describing the spatial and temporal interactions between pathways (e.g., whether the signals are processed sequentially or concomitantly when two pathways are required for a specific outcome). To address the extent of cross-talk between the major metazoan signaling pathways, we characterized immediate transcriptional responses to either single- or multiple pathway stimulations in homogeneous Drosophila cell lines. Our study, focusing on seven core pathways, epidermal growth factor receptor (EGFR), bone morphogenetic protein (BMP), Jun kinase (JNK), JAK/STAT, Notch, Insulin, and Wnt, revealed that many ligands and receptors are primary targets of signaling pathways, highlighting that transcriptional regulation of genes encoding pathway components is a major level of signaling cross-talk. In addition, we found that ligands and receptors can integrate multiple pathway activities and adjust their transcriptional responses accordingly. RNA-seq data is for JAK STAT pathway only
2018-12-01 | GSE123167 | GEO