Identification of epigenetic regulators of fibrotic transformation in cardiac fibroblasts through bulk and single-cell CRISPR screens (RNA-seq)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE281871 | GEO | 2025/09/12
REPOSITORIES: GEO
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Project description:Cardiac fibrosis is mediated by the persistent activity of myofibroblasts, which differentiate from resident cardiac fibroblasts in response to tissue damage and stress signals. The signaling pathways and transcription factors regulating fibrotic transformation have been thoroughly studied. By contrast, the roles of chromatin factors in fibroblast differentiation and their contribution to pathogenic cardiac fibrosis remain poorly understood. Here, we have combined bulk and single-cell CRISPR screens to characterize the roles of chromatin factors in ex vivo fibroblast differentiation. We uncover strong regulators of fibrotic states including Srcap and Tip60 chromatin remodelers, the NSL complex and the co-factors Hcfc1 and Wdr82. We confirm these factors are required for cellular processes underlying fibrosis including collagen synthesis and cell contractility. We use epigenetic profiling to demonstrate these chromatin factors facilitate the activity of pro-fibrotic transcription factors. Finally, using chemical perturbation in primary human cardiac fibroblasts we suggest Tip60 inhibition as a potential therapeutic approach for cardiac fibrosis.
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Project description:Cardiac fibrosis is mediated by the persistent activity of myofibroblasts, which differentiate from resident cardiac fibroblasts in response to tissue damage and stress signals. The signaling pathways and transcription factors regulating fibrotic transformation have been thoroughly studied. By contrast, the roles of chromatin factors in fibroblast differentiation and their contribution to pathogenic cardiac fibrosis remain poorly understood. Here, we have combined bulk and single-cell CRISPR screens to characterize the roles of chromatin factors inex vivofibroblast differentiation. We uncover strong regulators of fibrotic states including Srcap and Tip60 chromatin remodelers, the NSL complex and the co-factors Hcfc1 and Wdr82. We confirm these factors are required for cellular processes underlying fibrosis including collagen synthesis and cell contractility. We use epigenetic profiling to demonstrate these chromatin factors facilitate the activity of pro-fibrotic transcription factors. Finally, using chemical perturbation in primary human cardiac fibroblasts we suggest Tip60 inhibition as a potential therapeutic approach for cardiac fibrosis.
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Project description:Cardiac fibrosis is mediated by the persistent activity of myofibroblasts, which differentiate from resident cardiac fibroblasts in response to tissue damage and stress signals. The signaling pathways and transcription factors regulating fibrotic transformation have been thoroughly studied. By contrast, the roles of chromatin factors in fibroblast differentiation and their contribution to pathogenic cardiac fibrosis remain poorly understood. Here, we have combined bulk and single-cell CRISPR screens to characterize the roles of chromatin factors inex vivofibroblast differentiation. We uncover strong regulators of fibrotic states including Srcap and Tip60 chromatin remodelers, the NSL complex and the co-factors Hcfc1 and Wdr82. We confirm these factors are required for cellular processes underlying fibrosis including collagen synthesis and cell contractility. We use epigenetic profiling to demonstrate these chromatin factors facilitate the activity of pro-fibrotic transcription factors. Finally, using chemical perturbation in primary human cardiac fibroblasts we suggest Tip60 inhibition as a potential therapeutic approach for cardiac fibrosis.
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Project description:Cardiac fibrosis is mediated by the persistent activity of myofibroblasts, which differentiate from resident cardiac fibroblasts in response to tissue damage and stress signals. The signaling pathways and transcription factors regulating fibrotic transformation have been thoroughly studied. By contrast, the roles of chromatin factors in fibroblast differentiation and their contribution to pathogenic cardiac fibrosis remain poorly understood. Here, we have combined bulk and single-cell CRISPR screens to characterize the roles of chromatin factors inex vivofibroblast differentiation. We uncover strong regulators of fibrotic states including Srcap and Tip60 chromatin remodelers, the NSL complex and the co-factors Hcfc1 and Wdr82. We confirm these factors are required for cellular processes underlying fibrosis including collagen synthesis and cell contractility. We use epigenetic profiling to demonstrate these chromatin factors facilitate the activity of pro-fibrotic transcription factors. Finally, using chemical perturbation in primary human cardiac fibroblasts we suggest Tip60 inhibition as a potential therapeutic approach for cardiac fibrosis.
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Project description:Cardiac fibrosis is mediated by the persistent activity of myofibroblasts, which differentiate from resident cardiac fibroblasts in response to tissue damage and stress signals. The signaling pathways and transcription factors regulating fibrotic transformation have been thoroughly studied. By contrast, the roles of chromatin factors in fibroblast differentiation and their contribution to pathogenic cardiac fibrosis remain poorly understood. Here, we have combined bulk and single-cell CRISPR screens to characterize the roles of chromatin factors inex vivofibroblast differentiation. We uncover strong regulators of fibrotic states including Srcap and Tip60 chromatin remodelers, the NSL complex and the co-factors Hcfc1 and Wdr82. We confirm these factors are required for cellular processes underlying fibrosis including collagen synthesis and cell contractility. We use epigenetic profiling to demonstrate these chromatin factors facilitate the activity of pro-fibrotic transcription factors. Finally, using chemical perturbation in primary human cardiac fibroblasts we suggest Tip60 inhibition as a potential therapeutic approach for cardiac fibrosis.
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2024-07-01 | GSE270788 | GEO
Project description:Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast crosstalk in human cardiac disease remains unexplored, and there are currently no approved treatments that directly target cardiac fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 45 donors, acutely infarcted, and chronically failing human hearts. We identified a disease-associated fibroblast trajectory marked by cell surface expression of fibroblast activator protein (FAP), which diverged into distinct myofibroblasts and pro-fibrotic fibroblast populations, the latter resembling matrifibrocytes. We lineage traced FAP fibroblasts in vivo and showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model tissue fibrosis and demonstrated that 3 different in vivo mouse models of cardiac injury were superior compared to cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin 1 beta (IL-1β) signaling drove the emergence of pro-fibrotic fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts, the IL-1β ligand in CCR2 monocytes and macrophages, and inhibited IL-1β signaling using a monoclonal antibody and showed fewer pro-fibrotic fibroblasts, decreased cardiac fibrosis, and improved cardiac function. Herein, we characterize fibroblast lineage diversification in the failing heart and showed a subset of macrophages signal to fibroblasts via IL-1β and rewire their gene regulatory network and differentiation trajectory towards a pro-fibrotic fibroblast phenotype. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.
2024-07-01 | GSE270904 | GEO
Project description:Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast crosstalk in human cardiac disease remains unexplored, and there are currently no approved treatments that directly target cardiac fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 45 donors, acutely infarcted, and chronically failing human hearts. We identified a disease-associated fibroblast trajectory marked by cell surface expression of fibroblast activator protein (FAP), which diverged into distinct myofibroblasts and pro-fibrotic fibroblast populations, the latter resembling matrifibrocytes. We lineage traced FAP fibroblasts in vivo and showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model tissue fibrosis and demonstrated that 3 different in vivo mouse models of cardiac injury were superior compared to cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin 1 beta (IL-1β) signaling drove the emergence of pro-fibrotic fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts, the IL-1β ligand in CCR2 monocytes and macrophages, and inhibited IL-1β signaling using a monoclonal antibody and showed fewer pro-fibrotic fibroblasts, decreased cardiac fibrosis, and improved cardiac function. Herein, we characterize fibroblast lineage diversification in the failing heart and showed a subset of macrophages signal to fibroblasts via IL-1β and rewire their gene regulatory network and differentiation trajectory towards a pro-fibrotic fibroblast phenotype. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.
2024-07-01 | GSE270875 | GEO
Project description:Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast crosstalk in human cardiac disease remains unexplored, and there are currently no approved treatments that directly target cardiac fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 45 donors, acutely infarcted, and chronically failing human hearts. We identified a disease-associated fibroblast trajectory marked by cell surface expression of fibroblast activator protein (FAP), which diverged into distinct myofibroblasts and pro-fibrotic fibroblast populations, the latter resembling matrifibrocytes. We lineage traced FAP fibroblasts in vivo and showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model tissue fibrosis and demonstrated that 3 different in vivo mouse models of cardiac injury were superior compared to cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin 1 beta (IL-1β) signaling drove the emergence of pro-fibrotic fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts, the IL-1β ligand in CCR2 monocytes and macrophages, and inhibited IL-1β signaling using a monoclonal antibody and showed fewer pro-fibrotic fibroblasts, decreased cardiac fibrosis, and improved cardiac function. Herein, we characterize fibroblast lineage diversification in the failing heart and showed a subset of macrophages signal to fibroblasts via IL-1β and rewire their gene regulatory network and differentiation trajectory towards a pro-fibrotic fibroblast phenotype. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.
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Project description:Although fibrosis depicts a reparative mechanism, maladaptation of the heart due to excessive production of extracellular matrix accelerates cardiac dysfunction. The anthraquinone Rhein was examined for its anti-fibrotic potency to mitigate cardiac fibroblast-to-myofibroblast transition (FMT). Primary human ventricular cardiac fibroblasts were subjected to hypoxia and characterized with proteomics, transcriptomics and cell functional techniques. Knowledge based analyses of the omics data revealed a modulation of fibrosis-associated pathways and cell cycle due to Rhein administration during hypoxia, whereas p53 and p21 were identified as upstream regulators involved in the manifestation of cardiac fibroblast phenotypes. Mechanistically, Rhein-mediated cellular effects were linked to the histone deacetylase (HDAC)-dependent acetylation status of p53 a posttranslational modification that acts protein stabilizing. Direct enzymatic testing revealed an inhibitory potency of Rhein for HDAC classes I/II. Functionally, Rhein inhibited collagen contraction in response to protein abundance of SMAD7, thus demonstrating its anti-fibrotic property in cardiac remodeling. In conclusion, this study identifies Rhein as a novel potent HDAC inhibitor and provides evidence that Rhein may contribute to the treatment of cardiac fibrosis as anti-fibrotic agent. As readily available drug with approved safety, repurposing of Rhein constitutes a promising potential therapeutic approach in the supplemental and protective intervention of cardiac fibrosis.
2020-03-23 | PXD016731 | Pride