Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE130313 | GEO | 2019/05/21
REPOSITORIES: GEO
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Project description:Systemic scleroderma (SSc) is an autoimmune disease which results in fibrotic production in the lung. Resultant SSC-pulmonary fibrosis is the main cause of mortality among SSc patients. From high throughput RNAi screening, we uncovered the ubiquitin E3 ligase KLHL42 as a potential pro-fibrotic mediator of TGFb-dependent fibrotic signaling in primary SSc lung fibroblasts. In this analysis, we sought to uncover putative substrates for KLHL42 by comparing SSc lung fibroblasts with control or KLHL42 siRNA prior to TGFb-treatment, lysis, and TUBE precipitation. The resultant pull-down was analyzed with LC-MS/MS.
2020-01-14 | MSV000084800 | MassIVE
Project description:Systemic sclerosis (SSc) is an autoimmune disease characterized by clinical heterogeneity, multi-organ involvement, and complex genetic risk. Here, we report the first multi-tissue meta-analysis of ten independent SSc gene expression datasets. We identify a common immune-fibrotic expression axis across all tissues that is associated with the most severe disease phenotypes. The coexpression patterns conserved across tissues and phenotypes were used to query functional genomic networks, which allowed us to identify common and tissue-specific disease drivers. We find evidence of pro-fibrotic macrophages (MØs) in SSc end-target organs. Prominent genes in the skin functional genomic network are associated with SSc genetic risk and are modulated by immunosuppressive treatment in clinical improvers. These data suggest the interactions between T lymphocytes and MØs are a critical driver of disease and implicate MØs as central to SSc pathogenesis. In total, this study presents a mechanism for fibrosis in SSc end-target tissues, a set of putative therapeutic targets for modulating SSc, and a framework for multi-tissue functional genomic studies of complex human disease.
2017-01-01 | GSE76806 | GEO
Project description:Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by excessive production and accumulation of extracellular matrix, leading to fibrosis of skin and other internal organs. However, the main cellular participants in SSc skin fibrosis remain incompletely understood. Here using differentiation trajectories at a single cell level, we demonstrate a dual source of extracellular matrix deposition in SSc skin from both myofibroblasts and endothelial-to-mesenchymal-transitioning cells (EndoMT). We further define a central role of Hippo pathway effectors in differentiation and homeostasis of myofibroblast and EndoMT, respectively, and show that myofibroblasts and EndoMTs act as central communication hubs that drive key pro-fibrotic signaling pathways in SSc. Together, our data help characterize myofibroblast differentiation and EndoMT phenotypes in SSc skin, and hint that modulation of the Hippo pathway may contribute in reversing the pro-fibrotic phenotypes in myofibroblasts and EndoMTs.
2023-12-06 | GSE249279 | GEO
Project description:Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis
| PRJNA535485 | ENA
Project description:Objectives. Interleukin-17A (IL-17A) levels are increased in SSc skin and other organs but its role in fibrosis development is highly debated. Since epithelial cells are preferential targets of IL-17A, we aimed at investigating the role of IL-17A in the interactions between epidermis and dermis. Methods. Organotypic cultures of HD full human skin were challenged with IL-17A,TNF and TGF-β. Inflammatory mediators and type I collagen (col-I) levels were quantified. IL-17A- and TGF-β-induced changes in gene expression in full human skin were analysed by RNA sequencing. Results. In full human skin, TGF-β induced pro-fibrotic gene signature dominated by Wnt signalling. While IL-17A strongly promoted expression of many pro-inflammatory genes, it did not affect collagen gene levels but decreased Wnt signalling. At the protein level, IL-17A showed direct anti-fibrotic effects, as well as decreased by 2-fold TGF-β-triggered col-I production. Conclusions. We report here firstly, a novel model of fibrotic skin and secondly, that IL-17A acts as a potent anti-fibrotic factor in the full human skin. Furthermore, we show that IL-17A not only decreased ECM deposition by itself, but also counteracted TGF-β pro-fibrotic activities. Thus, IL-17A seems to play a dual role in SSc skin – strongly pro-inflammatory but anti-fibrotic, being an example that fibrosis and inflammation, although closely related, are two different processes. These data may help in directing and interpreting therapeutic approaches in SSc, since both, IL-17A and TGF-β, are target candidates in clinical trials.
2020-02-11 | GSE122305 | GEO
Project description:Systemic sclerosis (SSc) is a chronic autoimmune disease characterized with fibrosis of skin and multiple vital organs, but the immunological pathogenesis of SSc remains largely unknown. We show here that microRNA-19b (miR-19b) promotes IL-9-producing CD4+ T cells (Th9) that exacerbate SSc. Specifically, TGF-b plus IL-4 induced expression of TNF receptor associated factor 6 (TRAF6) through phosphorylated Smad3 linker region site Serine 213 (p-Smad3L-Ser213) and activated it through K63 ubiquitination by suppressing the leucine-rich-repeat-containing protein 3 (NLRC3). TRAF6 consequently formed complex with and activated TGF-b activated kinase 1 (TAK1). TAK1 promoted nuclear factor kappa B (NFκB) p65 activation, which then specifically upregulated miR-19b. miR-19b activated Il9 gene expression and promoted Th9 differentiation by directly targeting and suppressing atypical E2F family member E2f8 gene, a repressor for Il9 gene transcription. Importantly, Th9 cells played a critical role in the development and pathogenesis of experimental SSc by promoting the fibrosis in mice induced with Bleomycin. miR-19b and IL-9 were increased in CD4+ T cells in experimental SSc in mice and also in patients with SSc. Strikingly, inhibition of miR-19b resulted in fewer Th9 cells and attenuated fibrotic manifestations and ameliorated the disease in SSc mice. Our study identifies miR-19b as a key factor of Th9 cells that are involved in the pathogenesis of SSc. Our findings should have clinical implications for patients with SSc.
2024-08-21 | GSE269954 | GEO
Project description:Objectives: Scleroderma (systemic sclerosis, SSc), as a prototypic inflammation-driven fibrotic disease, possesses connective tissue lesions populated with persistently activated myofibroblasts maintained by an mechanotranductive/pro-adhesive signaling loop. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol has recently been identified as a YAP1 inhibitor: however, if celastrol can alleviate SSc fibrosis is unknown. Methods: Human dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor b1 (TGFb1) in the presence or absence of celastrol. C57BL6J mice were subjected to the inflammatory-driven bleomycin-induced model of skin SSc, in the presence or absence of celastrol. RNA expression was assessed using RNAseq, real-time polymerase chain reaction and spatial transcriptomic analyses. Protein expression was determined using Western blot and enzyme-linked immunosorbent assay. Fibrosis was monitored by hematoxylin and eosin and trichrome staining, and indirect immunofluorescence analysis. Results: In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including the induction of cellular communication network factor 2 (CCN2), collagen I and TGFβ1 protein. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of SSc dermatopathology, celastrol inhibited fibrosis and blocked nuclear localization of YAP in myofibroblasts. Conclusion: Our data are consistent with the hypothesis that compounds, such as celastrol, that antagonize the YAP pathway may be potential treatments for SSc skin fibrosis.
2023-11-01 | GSE226760 | GEO
Project description:Skin and lung fibrosis in systemic sclerosis (SSc) is driven by myofibroblasts, alpha-smooth muscle actin (SMA) expressing cells that produce matrix as well as increase tension on surrounding tissues. Myofibroblast progenitors have been described to arise from a variety of cell types in murine fibrosis models, but relatively modest insight is available as to their source and differentiation in fibrotic human diseases. We utilize single cell RNA-sequencing to examine the transcriptome changes that occur in fibroblasts in SSc skin and during myofibroblast differentiation. We show that dermal myofibroblasts arise from an SFRP2/DPP4-expressing progenitor fibroblast population. In SSc skin, fibroblasts undergo global changes in gene expression, including SFRP2-expressing fibroblasts, which globally upregulate expression of markers, such as PRSS23 and THBS1. However, only a fraction of SSc fibroblasts differentiate into myofibroblasts, as shown by expression of additional markers, such as SFRP4 and FNDC1. These results indicate that myofibroblasts derive from a specific fibroblast subpopulation in SSc skin, that their differentiation proceeds in two stages and that other fibroblast populations also shift transcriptomes in SSc skin, suggesting a cytokine driven process. The myofibroblast transcriptome implicates upstream transcription factors that should help further unravel the drivers of myofibroblast differentiation.
2021-05-20 | GSE138669 | GEO
Project description:Fibrotic diseases impose a major socioeconomic challenge on modern societies with limited treatment options. Adropin, a peptide hormone encoded by the energy-homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize Adropin/ENHO as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent downregulation of Adropin/ENHO in SSc skin across different SSc cohorts. The prototypical profibrotic cytokine TGFβ reduced Adropin/ENHO expression in a JNK-dependent manner. Restoration of Adropin signaling by therapeutic application of bioactive Adropin34-76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, the mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices (PCSS). Knockdown of GPR19, receptor of Adropin, abrogated the antifibrotic effects of Adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of Adropin34-76 were functionally linked to deactivation of GLI1 dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo and ex vivo. ChIP-seq confirmed Adropin34-76-induced changes in TGFβ/GLI1 signaling. Our study thus characterizes the TGFβ-induced downregulation of Adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling. We also provide evidence in multiple preclinical models that Adropin34-76 might offer potential for the treatment of fibrosis.
2024-04-29 | GSE252425 | GEO
Project description:Fibrotic diseases impose a major socioeconomic challenge on modern societies with limited treatment options. Adropin, a peptide hormone encoded by the energy-homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize Adropin/ENHO as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent downregulation of Adropin/ENHO in SSc skin across different SSc cohorts. The prototypical profibrotic cytokine TGFβ reduced Adropin/ENHO expression in a JNK-dependent manner. Restoration of Adropin signaling by therapeutic application of bioactive Adropin34-76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, the mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices (PCSS). Knockdown of GPR19, receptor of Adropin, abrogated the antifibrotic effects of Adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of Adropin34-76 were functionally linked to deactivation of GLI1 dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo and ex vivo. ChIP-seq confirmed Adropin34-76-induced changes in TGFβ/GLI1 signaling. Our study thus characterizes the TGFβ-induced downregulation of Adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling. We also provide evidence in multiple preclinical models that Adropin34-76 might offer potential for the treatment of fibrosis.
2024-04-29 | GSE252139 | GEO