The Fosl1-Kdm6b Axis Controls Skeletal Muscle Fibrosis by Regulating Histone H3K27me3 [Cut&Tag]
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ABSTRACT:
PROVIDER: PRJNA1149680 | ENA |
REPOSITORIES: ENA
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Project description:Skeletal muscle fibrosis, characterized by the replacement of functional muscle tissue with fibrotic scarring, leads to muscle function loss and potentially fatal respiratory failure, particularly in muscular dystrophy. The mechanisms driving muscle fibrosis is not yet fully understood. Our study utilized single-cell RNA-seq and single-nuclei ATAC-seq to analyze the transcriptome and chromatin accessibility of regenerating and dystrophic skeletal muscle, identifying a specific subset of fibro-adipogenic precursors (FAPs) enriched in dystrophic muscles, termed fibrotic FAPs. We further demonstrated that chronic inflammation upregulates Fosl1, an early response gene, which activates the expression of Kdm6b in fibrotic FAPs. Kdm6b, a histone demethylase, specifically removes the repressive histone H3K27me3 mark. Notably, targeting Kdm6b genetically and pharmacologically inhibits fibrotic di^erentiation in human and mouse FAPs in vitro and ameliorated muscle fibrosis in mouse models in vivo. Furthermore, constitutive activation of the Fosl1-Kdm6b pathway reduced H3K27me3 modification at critical fibrotic gene loci, leading to their transcriptional activation. Taken together, our findings reveal that chronic inflammation perpetuates the Fosl1-Kdm6b axis in FAPs, causing epigenomic reprogramming and altering the H3K27me3 landscape, which is essential for preventing fibrotic di^erentiation of FAPs and skeletal muscle fibrosis.
2025-02-28 | GSE275142 | GEO
Project description:Skeletal muscle fibrosis, characterized by the replacement of functional muscle tissue with fibrotic scarring, leads to muscle function loss and potentially fatal respiratory failure, particularly in muscular dystrophy. The mechanisms driving muscle fibrosis is not yet fully understood. Our study utilized single-cell RNA-seq and single-nuclei ATAC-seq to analyze the transcriptome and chromatin accessibility of regenerating and dystrophic skeletal muscle, identifying a specific subset of fibro-adipogenic precursors (FAPs) enriched in dystrophic muscles, termed fibrotic FAPs. We further demonstrated that chronic inflammation upregulates Fosl1, an early response gene, which activates the expression of Kdm6b in fibrotic FAPs. Kdm6b, a histone demethylase, specifically removes the repressive histone H3K27me3 mark. Notably, targeting Kdm6b genetically and pharmacologically inhibits fibrotic di^erentiation in human and mouse FAPs in vitro and ameliorated muscle fibrosis in mouse models in vivo. Furthermore, constitutive activation of the Fosl1-Kdm6b pathway reduced H3K27me3 modification at critical fibrotic gene loci, leading to their transcriptional activation. Taken together, our findings reveal that chronic inflammation perpetuates the Fosl1-Kdm6b axis in FAPs, causing epigenomic reprogramming and altering the H3K27me3 landscape, which is essential for preventing fibrotic differentiation of FAPs and skeletal muscle fibrosis.
2025-02-28 | GSE275143 | GEO
Project description:Skeletal muscle fibrosis, characterized by the replacement of functional muscle tissue with fibrotic scarring, leads to muscle function loss and potentially fatal respiratory failure, particularly in muscular dystrophy. The mechanisms driving muscle fibrosis is not yet fully understood. Our study utilized single-cell RNA-seq and single-nuclei ATAC-seq to analyze the transcriptome and chromatin accessibility of regenerating and dystrophic skeletal muscle, identifying a specific subset of fibro-adipogenic precursors (FAPs) enriched in dystrophic muscles, termed fibrotic FAPs. We further demonstrated that chronic inflammation upregulates Fosl1, an early response gene, which activates the expression of Kdm6b in fibrotic FAPs. Kdm6b, a histone demethylase, specifically removes the repressive histone H3K27me3 mark. Notably, targeting Kdm6b genetically and pharmacologically inhibits fibrotic di^erentiation in human and mouse FAPs in vitro and ameliorated muscle fibrosis in mouse models in vivo. Furthermore, constitutive activation of the Fosl1-Kdm6b pathway reduced H3K27me3 modification at critical fibrotic gene loci, leading to their transcriptional activation. Taken together, our findings reveal that chronic inflammation perpetuates the Fosl1-Kdm6b axis in FAPs, causing epigenomic reprogramming and altering the H3K27me3 landscape, which is essential for preventing fibrotic differentiation of FAPs and skeletal muscle fibrosis.
2025-02-28 | GSE275141 | GEO
Project description:Skeletal muscle fibrosis, characterized by the replacement of functional muscle tissue with fibrotic scarring, leads to muscle function loss and potentially fatal respiratory failure, particularly in muscular dystrophy. The mechanisms driving muscle fibrosis is not yet fully understood. Our study utilized single-cell RNA-seq and single-nuclei ATAC-seq to analyze the transcriptome and chromatin accessibility of regenerating and dystrophic skeletal muscle, identifying a specific subset of fibro-adipogenic precursors (FAPs) enriched in dystrophic muscles, termed fibrotic FAPs. We further demonstrated that chronic inflammation upregulates Fosl1, an early response gene, which activates the expression of Kdm6b in fibrotic FAPs. Kdm6b, a histone demethylase, specifically removes the repressive histone H3K27me3 mark. Notably, targeting Kdm6b genetically and pharmacologically inhibits fibrotic di^erentiation in human and mouse FAPs in vitro and ameliorated muscle fibrosis in mouse models in vivo. Furthermore, constitutive activation of the Fosl1-Kdm6b pathway reduced H3K27me3 modification at critical fibrotic gene loci, leading to their transcriptional activation. Taken together, our findings reveal that chronic inflammation perpetuates the Fosl1-Kdm6b axis in FAPs, causing epigenomic reprogramming and altering the H3K27me3 landscape, which is essential for preventing fibrotic di^erentiation of FAPs and skeletal muscle fibrosis.
2025-02-28 | GSE275140 | GEO
Project description:The Fosl1-Kdm6b Axis Controls Skeletal Muscle Fibrosis by Regulating Histone H3K27me3 [HiCAR]
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Project description:The Fosl1-Kdm6b Axis Controls Skeletal Muscle Fibrosis by Regulating Histone H3K27me3 [scRNA-seq]
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Project description:The H3K27me2/me3 histone demethylase KDM6B is over-expressed in neuroblastoma and is essential to neuroblastoma cell survival. While the KDM6B inhibitor, GSK-J4, has shown activity in in vitro and in vivo preclinical models, the mechanism of action remains poorly defined. We demonstrate that genetic and pharmacologic inhibition of KDM6B downregulates the pRB-E2F transcriptome and MYCN expression. Chemical genetic analyses show that high expression of the E2F transcriptome is positively correlated with sensitivity of cancer cells to GSK-J4. Mechanistically, inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and GSK-J4. A gene signature targeted by KDM6B inhibition is associated with poor survival of patients with neuroblastoma regardless of the MYCN status. These data indicate that KDM6B activity promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.
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2022-02-01 | GSE185098 | GEO
Project description:To explore genome-wide alteration MED1 and FOSL1 after depletion of FOSL1, we performed chromatin immunoprecipitation sequencing (ChIP-seq) of SCC1 cells to examine genome-wide recruitment of MED1 and FOSL1 following FOSL1 knockdown. Depletion of FOSL1 led to dramatically loss of the recruitment of MED1 and FOSL1 at a cohort of key oncogenes associate with tumorigenesis and metastasis.
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