H3K4 demethylase KDM5B regulates epigenetic plasticity and cancer cell identity
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PROVIDER: PRJNA698662 | ENA |
REPOSITORIES: ENA
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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.
2022-05-19 | GSE165957 | GEO
Project description:H3K4 demethylase KDM5B regulates epigenetic plasticity and cancer cell identity [ChIP-seq]
| PRJNA698669 | ENA
Project description:H3K4 demethylase KDM5B regulates epigenetic plasticity and cancer cell identity [RNA-seq]
| PRJNA698668 | ENA
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
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.
2014-01-27 | E-GEOD-53087 | biostudies-arrayexpress
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. RNA-Seq of murine shLuc and shKdm5b ES cells differentiated for 72h in the absence of LIF.
2014-01-27 | E-GEOD-53090 | biostudies-arrayexpress
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.
2014-01-27 | GSE53090 | GEO
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.
2014-01-27 | GSE53087 | GEO
Project description:Positioning of nucleosomes along DNA is an integral regulator of chromatin accessibility and gene expression in diverse cell types. However, the precise nature of how post-translational modification of histones such as activating trimethylated histone 3 lysine 4 (H3K4me3), or histone demethylases including the H3K4 demethylase, KDM5B, impacts nucleosome positioning around transcriptional start sites (TSS) of active genes is poorly understood. Here, we report that KDM5B is a critical regulator of nucleosome positioning in embryonic stem (ES) cells. Micrococcal nuclease sequencing (MNase-Seq) revealed increased enrichment of nucleosomes around TSS regions and DNase I hypersensitive sites in KDM5B-depleted ES cells. Moreover, depletion of KDM5B resulted in a widespread redistribution and disorganization of nucleosomes in a sequence-dependent manner. Dysregulated nucleosome phasing was also evident in KDM5B-depleted ES cells, including asynchronous nucleosome spacing surrounding TSS regions, where nucleosome variance was positively correlated with the degree of asynchronous phasing. The redistribution of nucleosomes around TSS regions in KDM5B-depleted ES cells is correlated with dysregulated gene expression, and altered H3K4me3 and RNA polymerase II occupancy. In addition, we found that DNA shape features varied significantly at regions with shifted nucleosomes. Altogether, our data support a role for KDM5B in regulating nucleosome positioning in ES cells.
2019-04-23 | GSE123249 | GEO