Sex specific role of KDM5B demethylase in Alcohol-associated Liver Disease development and resolution
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ABSTRACT:
PROVIDER: PRJNA1021978 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26204354_1.fastq.gz | Fastqsanger.gz | |||
| SRR26204354_2.fastq.gz | Fastqsanger.gz | |||
| SRR26204355_1.fastq.gz | Fastqsanger.gz | |||
| SRR26204355_2.fastq.gz | Fastqsanger.gz | |||
| SRR26204356_1.fastq.gz | Fastqsanger.gz |
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Project description:Alcohol-associated liver disease (ALD) is a major cause of alcohol related mortality. Recently we identified hepatic demethylases KDM5B and KDM5C as important sex-specific epigenetic regulators of alcohol response in the liver. In this study we aimed to study the molecular mechanisms of KDM5-dependent ALD development and resolution. We found that alcohol induces pathological changes in cell-cell communication in the liver that are in part mediated by epigenetic changes in hepatocytes mediated by histone demethylase KDM5B. Using cell type specific knockout mice, we found that KDM5B histone demethylase was a key regulator of alcohol-induced epigenetic changes in hepatocytes. Moreover, it regulated hepatocytes-non-parenchymal cell crosstalk that promoted inflammation and fibrosis development in ALD. This mechanism was specific to females. In males KDM5B deficiency was not sufficient to prevent fibrosis development. In contrast KDM5B demethylase loss promoted fibrosis resolution in both males and females. This mechanism involved changes in hepatocyte-macrophage crosstalk and LXRα activation, which we identified to be critical for the fibrosis resolution process. CONCLUSION: In summary, KDM5B demethylase is a regulator of cell-cell crosstalk involved in disease progression in females and in disease resolution in both sexes.
2023-10-07 | GSE244240 | GEO
Project description:Alcohol-associated liver disease (ALD) is a major cause of alcohol related mortality. The specific mechanisms responsible for ALD development and progression are not fully understood, and there is limited therapy for any stage of ALD. Sex differences are often disregarded in in genetic and mechanistic studies. We aimed to take an unbiased approach to define sex specific pathways in livers exposed to alcohol. METHODS: Mice were fed LieberDeCarli alcohol liquid diet for 3 weeks. To identify the role of Kdm5b and Kdm5c we injected mice with AAV-shControl at 2x10^11 gc per mouse or AAV-shKdm5b and AAV-Kdm5c vectors at 10^11 gc per mouse. To assess the role of AhR we injected mice with AAV-shControl or AAV-shAhR vectors at 10^11 gc per mouse. RESULTS: We found several pathways affected by alcohol in sex specific way and identified KDM5 demethylases as contributors to that specificity.
2022-02-08 | GSE195889 | GEO
Project description:Purpose: Advanced melanoma patients have poor prognosis. Although immune checkpoint blockade has revolutionized treatment for melanoma patients, majority of patients do not respond. The goal of this research is to evaluate whether epigenetic therapy targeting KDM5B could overcome resistance to immunotherapy. Methods:RNA-Seq analysis of KDM5B KO mouse melanoma cell lines compared to control cells to evaluate whether KDM5B depletion induces activation of retroelements, which subsequently activates type I interferon responses. Mouse studies were conducted to evaluate whether anti-tumor immunity induced by KDM5B loss could overcome immunotherapy resistance. Results: We identified that KDM5B depletion derepress retroelement expression, which subsequently activates type I interferon response and enhances anti-tumor immunity. Loss of KDM5B could overcome resistance to anti-PD-1 immunotherapy. Conclusions: Our work characterized ablation of histone demethylase KDM5B in melanoma augments anti-tumor immunity through Upregulation of retroelements.
2021-07-25 | GSE161063 | GEO
Project description:Purpose: Advanced melanoma patients have poor prognosis. Although immune checkpoint blockade has revolutionized treatment for melanoma patients, majority of patients do not respond. The goal of this research is to evaluate whether epigenetic therapy targeting KDM5B could overcome resistance to immunotherapy. Methods:RNA-Seq analysis of KDM5B KO mouse melanoma cell lines compared to control cells to evaluate whether KDM5B depletion induces activation of retroelements, which subsequently activates type I interferon responses. Mouse studies were conducted to evaluate whether anti-tumor immunity induced by KDM5B loss could overcome immunotherapy resistance. Results: We identified that KDM5B depletion derepress retroelement expression, which subsequently activates type I interferon response and enhances anti-tumor immunity. Loss of KDM5B could overcome resistance to anti-PD-1 immunotherapy. Conclusions: Our work characterized ablation of histone demethylase KDM5B in melanoma augments anti-tumor immunity through Upregulation of retroelements.
2021-07-25 | GSE161064 | GEO
Project description:The H3K4 demethylase KDM5B is overexpressed in multiple cancer types, but the underlying mechanistic contribution of dysregulated H3K4 demethylation in cancer is poorly understood. Here, we show that depletion of KDM5B in multiple types of cancer cells leads to increased proliferation, decreased heterogeneity, and phenotype changes consistent with a de-differentiated or stem cell-like phenotype. Our results also support a role for KDM5B in regulating epigenetic plasticity, where loss of KDM5B in cancer cell lines with elevated KDM5B expression leads to permissive or repressive chromatin states, which facilitate activation or repression of alternative transcriptional programs. KDM5B depleted cancer cells exhibited altered epigenetic and transcriptional profiles resembling a more primitive cellular state. Genome-wide maps of H3K4me3 across a compendium of KDM5B-depleted cancer cell lines revealed altered distributions of canonical and broad H3K4me3 domains at promoters of tumor suppressors. Genes with altered H3K4me3 in KDM5B-depleted cancer cells were enriched with tumor suppressors and housekeeping genes. While high expression of KDM5B is associated with poor clinical outcomes, findings from this study suggest that targeted inhibition of KDM5B as a therapeutic strategy may not be sufficient to inhibit growth of cancer cells as KDM5B regulates H3K4 methylation at a wide range of genes, but does so in a context-dependent manner. This study also provides a resource for evaluating associations between alterations in epigenetic patterning of H3K4 methylation and transcriptome profiles in a diverse set of cancer cells.
2022-05-19 | GSE165958 | GEO
Project description:The H3K4 demethylase KDM5B is overexpressed in multiple cancer types, but the underlying mechanistic contribution of dysregulated H3K4 demethylation in cancer is poorly understood. Here, we show that depletion of KDM5B in multiple types of cancer cells leads to increased proliferation, decreased heterogeneity, and phenotype changes consistent with a de-differentiated or stem cell-like phenotype. Our results also support a role for KDM5B in regulating epigenetic plasticity, where loss of KDM5B in cancer cell lines with elevated KDM5B expression leads to permissive or repressive chromatin states, which facilitate activation or repression of alternative transcriptional programs. KDM5B depleted cancer cells exhibited altered epigenetic and transcriptional profiles resembling a more primitive cellular state. Genome-wide maps of H3K4me3 across a compendium of KDM5B-depleted cancer cell lines revealed altered distributions of canonical and broad H3K4me3 domains at promoters of tumor suppressors. Genes with altered H3K4me3 in KDM5B-depleted cancer cells were enriched with tumor suppressors and housekeeping genes. While high expression of KDM5B is associated with poor clinical outcomes, findings from this study suggest that targeted inhibition of KDM5B as a therapeutic strategy may not be sufficient to inhibit growth of cancer cells as KDM5B regulates H3K4 methylation at a wide range of genes, but does so in a context-dependent manner. This study also provides a resource for evaluating associations between alterations in epigenetic patterning of H3K4 methylation and transcriptome profiles in a diverse set of cancer cells.
2022-05-19 | GSE165957 | GEO
Project description:Purpose: Advanced melanoma patients have poor prognosis. Although immune checkpoint blockade has revolutionized treatment for melanoma patients, majority of patients do not respond. The goal of this research is to evaluate whether epigenetic therapy targeting KDM5B could overcome resistance to immunotherapy. Methods:ChIP-Seq analysis of KDM5B binding on retroelements in mouse melanoma cell line YUMMER1.7. Results: We identified that KDM5B directly bind to retreoelements to repress their expression. Conclusions: Our work characterized ablation of histone demethylase KDM5B in melanoma augments anti-tumor immunity through Upregulation of retroelements.
2021-07-25 | GSE175542 | GEO
Project description:Purpose: Advanced melanoma patients have poor prognosis. Although immune checkpoint blockade has revolutionized treatment for melanoma patients, majority of patients do not respond. The goal of this research is to evaluate whether epigenetic therapy targeting KDM5B could overcome resistance to immunotherapy. Methods:ChIP-Seq analysis of KDM5B binding on retroelements in mouse melanoma cell line 1445. Results: We identified that KDM5B directly bind to retreoelements to repress their expression. Conclusions: Our work characterized ablation of histone demethylase KDM5B in melanoma augments anti-tumor immunity through Upregulation of retroelements.
2021-07-25 | GSE161062 | GEO
Project description:Purpose: Advanced melanoma patients have poor prognosis. Although immune checkpoint blockade has revolutionized treatment for melanoma patients, majority of patients do not respond. The goal of this research is to evaluate whether epigenetic therapy targeting KDM5B could overcome resistance to immunotherapy. Methods: ATAC-Seq analysis of mouse melanoma cell line YUMMER1.7. Results: We identified that KDM5B directly bind to retreoelements to repress their expression. Conclusions: Our work characterized ablation of histone demethylase KDM5B in melanoma augments anti-tumor immunity through Upregulation of retroelements.
2021-07-25 | GSE175574 | GEO
Project description:KDM5B histone demethylase is overexpressed in many cancers with an ambivalent role in oncogenesis which depends on the specific contest. A putative explanation of this ambivalence could be represented by the expression pattern of different protein isoforms with different functional roles which could be present at different levels in different cancer cell lines. We show here that one of these isoforms (NTT) accumulates in breast cancer cell lines up to 50-60% of the total, due to a remarkable protein stability relative to the canonical PLU-1 isoform which shows a much faster turnover. Mass Spectrometry (MS) profiling of histone post-translational modifications showed that overexpression of this isoform in MCF7 cells leads to an increase in H3K4 trimethylation. We discuss the relevance of this finding at the light of the hypothesis that KDM5B may possess regulatory roles independent of its catalytic activity.
2023-07-20 | PXD033337 | Pride