Sex specific role of KDM5B demethylase in Alcohol-associated Liver Disease development and resolution
Ontology highlight
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 |
Items per page: 5 1 - 5 of 54 |
Similar Datasets
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:Microglia maintain brain homeostasis through coordinated pathways, including cell migration, phagocytosis, and secretion of immune-related signaling factors. Microglial reactivity is associated with a variety of functional outcomes that are highly context-dependent with epigenetic regulation through DNA methylation and histone modificationsimplicated in this complex control of microglial plasticity. Specifically, in relation to histone methylation, lysine-specific demethylase 5B (KDM5B) has been associated with several pathophysiological states, including neurodevelopmental and inflammatory disorders, cancer, and alcohol use disorder; however, the cell-type-specific role of KDM5B in microglial reactivity has not been investigated. In this study, transcriptomic and proteomic analyses were used to characterize the effects of KDM5B depletion on microglial pathways in clustered regularly interspaced short palindromic repeats (CRISPR)-edited adult-derived murine microglial cells. Additionally, various immunomodulatory stimuli, including lipopolysaccharide, interleukin-4, and alcohol, were used to study the effects of KDM5B depletion on immune reactivity in microglia using deep proteomics and bioinformatic analysis. Through this comprehensive characterization, KDM5B-depleted microglia exhibited broad remodeling of immune reactivity, including reduced intracellular and secreted inflammatory responses to lipopolysaccharide as well as distinct modulation of alcohol- and interleukin-4-induced pathways, that was functionally demonstrated by altered cytokine secretion profiles. Results from this study provide critical insight into KDM5B-mediated immunological effects on microglial function.
2026-03-02 | PXD058485 | Pride
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 | GSE161064 | 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:Loss-of-function mutations in genes encoding lysine demethylases specific for trimethylated lysine 4 of histone 3 (H3K4me3) are associated with neurodevelopmental conditions, including autism spectrum disorder (ASD) and intellectual disability. To study the role of KDM5B (Lysine DeMethylase-5B)-mediated H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviours and increased brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex. Increased H3K4me3 levels at the promoter and associated expression of the Grin2d gene was associated with increased levels of NMDAR2D protein in synaptosomes isolated from the early postnatal Kdm5b-deficient neocortex. Treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalizations. These findings suggest that increased H3K4me3 levels and associated Grin2d gene upregulation disrupt brain development and function, leading to socio-communication deficits and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency.
2026-03-31 | GSE262555 | GEO
Project description:Loss-of-function mutations in genes encoding lysine methyltransferases (KMTs) and demethylases (KDMs) specific for trimethylated of lysine 4 of histone 3 (H3K4me3) are associated with neurodevelopmental conditions, including autism spectrum disorder and intellectual disability. To study the role of KDM5B (Lysine DeMethylase-5B)-mediated H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviours and increased brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex. These included elevated expression of Grin2d. The Grin2d gene product NMDAR2D was increased in synaptosomes isolated from the Kdm5b-deficient neocortex and treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalisations and reduced repetitive digging behaviours. These findings suggest that increased H3K4me3 levels and associated Grin2d gene upregulation disrupt brain development and function, leading to socio-communication deficits and repetitive behaviours, and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency.
2026-02-26 | GSE311802 | 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: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:Loss-of-function mutations in genes encoding lysine methyltransferases (KMTs) and demethylases (KDMs) specific for trimethylated of lysine 4 of histone 3 (H3K4me3) are associated with neurodevelopmental conditions, including autism spectrum disorder and intellectual disability. To study the role of KDM5B (Lysine DeMethylase-5B)-mediated H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviours and increased brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex. These included elevated expression of Grin2d. The Grin2d gene product NMDAR2D was increased in synaptosomes isolated from the Kdm5b-deficient neocortex and treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalisations and reduced repetitive digging behaviours. These findings suggest that increased H3K4me3 levels and associated Grin2d gene upregulation disrupt brain development and function, leading to socio-communication deficits and repetitive behaviours, and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency.
2026-03-31 | GSE316882 | GEO