Loss of KDM5B ameliorates pathological cardiac fibrosis and dysfunction by epigenetically enhancing ATF3 expression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE213746 | GEO | 2023/01/04
REPOSITORIES: GEO
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Project description:Myocardial fibrosis is the most common pathological feather of adverse ventricular remodeling, and persistent fibrotic extension decreases myocardial compliance, promotes the development of heart failure. Epigenetics has been considered to play a potent regulatory role in the development of excessive myocardial fibrosis. Although, the explicit mechanism of epigenetic regulation in myocardial fibrosis still needs to be fully elucidated.Transcriptome microarray analysis was used to screen differentially expressed genes in myocardial tissues from KDM5B KO and littermate control WT mice at day 7 after MI operation.
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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.
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Project description:ES cell pluripotency is thought to be regulated in part by H3K4 methylation. However, it is unclear how H3K4 demethylation contributes to ES cell function and participates in iPS cell reprogramming. Here, we show that KDM5B, which demethylates H3K4, is important for ES cell differentiation, and presents a barrier to the reprogramming process. Depletion of Kdm5b leads to an extension in the self-renewal of ES cells in the absence of LIF. Transcriptome analysis revealed the persistent expression of pluripotency-genes and underexpression of developmental genes during differentiation in the absence of Kdm5b, suggesting that KDM5B plays a key role in cellular fate changes. We also observed accelerated reprogramming of differentiated cells in the absence of Kdm5b, demonstrating that KDM5B is a barrier to the reprogramming process. Expression analysis revealed that mesenchymal master regulators associated with epithelial-to-mesenchymal transition (EMT) are downregulated during reprogramming in the absence of Kdm5b. Moreover, global analysis of H3K4me3/2 revealed that enhancers of fibroblast genes are rapidly deactivated in the absence of Kdm5b, and genes associated with EMT lose H3K4me3/2 during the early reprogramming process. These findings provide functional insight into the role for KDM5B in regulating ES cell differentiation and as a barrier to the reprogramming process. ChIP-Seq for H3K4me3 and H3K4me2 in murine shLuc and shKdm5b 4TF-MEFs (tetO-Pou5f1,-Sox2,-Klf4,-c-Myc) at 48h.
2013-10-14 | E-GEOD-47123 | biostudies-arrayexpress
Project description:ES cell pluripotency is thought to be regulated in part by H3K4 methylation. However, it is unclear how H3K4 demethylation contributes to ES cell function and participates in iPS cell reprogramming. Here, we show that KDM5B, which demethylates H3K4, is important for ES cell differentiation, and presents a barrier to the reprogramming process. Depletion of Kdm5b leads to an extension in the self-renewal of ES cells in the absence of LIF. Transcriptome analysis revealed the persistent expression of pluripotency-genes and underexpression of developmental genes during differentiation in the absence of Kdm5b, suggesting that KDM5B plays a key role in cellular fate changes. We also observed accelerated reprogramming of differentiated cells in the absence of Kdm5b, demonstrating that KDM5B is a barrier to the reprogramming process. Expression analysis revealed that mesenchymal master regulators associated with epithelial-to-mesenchymal transition (EMT) are downregulated during reprogramming in the absence of Kdm5b. Moreover, global analysis of H3K4me3/2 revealed that enhancers of fibroblast genes are rapidly deactivated in the absence of Kdm5b, and genes associated with EMT lose H3K4me3/2 during the early reprogramming process. These findings provide functional insight into the role for KDM5B in regulating ES cell differentiation and as a barrier to the reprogramming process. RNA-Seq of undifferentiated and embryoid body (EB) differentiated murine shLuc and shKdm5b ES cells
2013-10-14 | E-GEOD-47124 | biostudies-arrayexpress
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.
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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.
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Project description:Analysis of the effects of KDM5B in melanoma cells at gene expression level. Knockdown of KDM5B provides important information about potential target genes of KDM5B.
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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.
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Project description:Pluripotency of embryonic stem (ES) cells is controlled in part by chromatin-modifying factors that regulate histone H3 lysine 4 (H3K4) methylation. However, it remains unclear how H3K4 demethylation contributes to ES cell function. Here, we show that KDM5B, which demethylates lysine 4 of histone H3, co-localizes with H3K4me3 near promoters and enhancers of active genes in ES cells; its depletion leads to spreading of H3K4 methylation into gene bodies and enhancer shores, indicating that KDM5B functions to focus H3K4 methylation at promoters and enhancers. Spreading of H3K4 methylation to gene bodies and enhancer shores is linked to defects in gene expression programs and enhancer activity, respectively, during self-renewal and differentiation of KDM5B-depleted ES cells. KDM5B critically regulates H3K4 methylation at bivalent genes during differentiation in the absence of LIF or Oct4. We also show that KDM5B and LSD1, another H3K4 demethylase, co-regulate H3K4 methylation at active promoters but they retain distinct roles in demethylating gene body regions and bivalent genes. Our results provide global and functional insight into the role of KDM5B in regulating H3K4 methylation marks near promoters, gene bodies, and enhancers in ES cells and during differentiation. ChIP-Seq for KDM5B, H3K4 methylation and H3K27ac in murine shLuc, shKdm5b, shLuc-LSD1i, shKdm5b-LSD1i ES cells, and during differentiation of shLuc and shKdm5b ES cells for 2 days, 3 days, and 4 days without LIF.
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