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H3K4 demethylase KDM5B regulates epigenetic plasticity and cancer cell identity [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165958 | GEO | 2022/05/19

REPOSITORIES: GEO

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H3K4 demethylase KDM5B regulates epigenetic plasticity and cancer cell identity [ChIP-seq]

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

KDM5B focuses H3K4 methylation near promoters and enhancers during embryonic stem cell self-renewal and differentiation [ChIP-Seq]

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

KDM5B focuses H3K4 methylation near promoters and enhancers during embryonic stem cell self-renewal and differentiation [RNA-Seq]

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

KDM5B decommissions the H3K4 methylation landscape of self-renewal genes during trophoblast stem cell differentiation [RNA-seq]

Project description:Trophoblast stem (TS) cells derived from the trophectoderm (TE) of mammalian embryos have the ability to self-renew indefinitely or differentiate into fetal lineages of the placenta. Epigenetic control of gene expression plays an instrumental role in dictating the fate of TS cell self-renewal and differentiation. However, the roles of histone demethylases and activating histone modifications such as methylation of histone 3 lysine 4 (H3K4me3/me2) in regulating TS cell expression programs, and in priming the epigenetic landscape for trophoblast differentiation, are largely unknown. Here, we demonstrate that the H3K4 demethylase, KDM5B, regulates the H3K4 methylome and expression landscapes of TS cells. Depletion of KDM5B resulted in downregulation of TS cell self-renewal genes and upregulation of trophoblast-lineage genes, which was accompanied by altered H3K4 methylation. Moreover, we found that KDM5B resets the H3K4 methylation landscape during differentiation in the absence of the external self-renewal signal, FGF4, by removing H3K4 methylation from promoters of self-renewal genes, and of genes whose expression is enriched in TS cells. Altogether, our data indicate an epigenetic role for KDM5B in regulating H3K4 methylation in TS cells and during trophoblast differentiation.

2018-06-14 | GSE111847 | GEO

KDM5B decommissions the H3K4 methylation landscape of self-renewal genes during trophoblast stem cell differentiation [ChIP-seq]

2018-06-14 | GSE111846 | GEO

Extended self-renewal and accelerated reprogramming in the absence of Kdm5b [ChIP-Seq]

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

Contribution of H3K4 demethylase KDM5B to nucleosome organization in embryonic stem cells revealed by micrococcal nuclease sequencing

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.

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H3K4 demethylase KDM5B regulates global dynamics of transcription elongation and alternative splicing in embryonic stem cells [RNA-seq]

Project description:Epigenetic regulation of chromatin plays a critical role in controlling embryonic stem (ES) cell self-renewal and pluripotency. However, the roles of histone demethylases and activating histone modifications such as trimethylated histone 3 lysine 4 (H3K4me3) in transcriptional events such as RNA polymerase II (RNAPII) elongation and alternative splicing are largely unknown. In this study, we show that KDM5B, which demethylates H3K4me3, plays an integral role in regulating RNAPII occupancy, transcriptional initiation and elongation, and alternative splicing events in ES cells. Depletion of KDM5B leads to altered RNAPII promoter occupancy, and decreased RNAPII initiation and elongation rates at active genes and at genes marked with broad H3K4me3 domains. Moreover, our results demonstrate that spreading of H3K4me3 from promoter to gene body regions, which is mediated by depletion of KDM5B, modulates RNAPII elongation rates and RNA splicing in ES cells. We further show that KDM5B is enriched nearby alternatively spliced exons, and depletion of KDM5B leads to altered levels of H3K4 methylation in alternatively spliced exon regions, which is accompanied by differential expression of these ASEs. Altogether, our data indicate an epigenetic role for KDM5B in regulating RNAPII elongation and alternative splicing, which may support the diverse mRNA repertoire in ES cells.

2017-04-13 | GSE95074 | GEO

H3K4 demethylase KDM5B regulates global dynamics of transcription elongation and alternative splicing in embryonic stem cells [ChIP-seq]

2017-04-13 | GSE94739 | GEO

Extended self-renewal and accelerated reprogramming in the absence of Kdm5b [RNA-Seq]

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

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