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Dynamic of H3K4me3-broad domains uncover an epigenetic switch between cell identity and cancer-related genes

ABSTRACT: Dynamic of H3K4me3-broad domains uncover an epigenetic switch between cell identity and cancer-related genes

PROVIDER: PRJNA635406 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11858501.fastq.gz	Fastqsanger.gz
	SRR11858502.fastq.gz	Fastqsanger.gz
	SRR11858503.fastq.gz	Fastqsanger.gz
	SRR11858504.fastq.gz	Fastqsanger.gz
	SRR11858505.fastq.gz	Fastqsanger.gz

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Dynamic of broad H3K4me3 domains uncover an epigenetic switch between cell identity and cancer-related genes

Project description:Dynamic of broad H3K4me3 domains uncover an epigenetic switch between cell identity and cancer-related genes

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Dynamic of H3K4me3-broad domains uncover an epigenetic switch between cell identity and cancer-related genes

Project description:Broad domains of H3K4 methylation have been associated with tissue specific, cell identity and tumor suppressor genes. Here, we identified broad H3K4me3 domains (BH4D)-associated genes in human thymic T cell populations and a collection of T-Acute Lymphoblastic Leukemia (T-ALL) primary samples and cell lines. We found that BH4D are highly dynamic throughout T cell differentiation, flag key leukemia associated oncogenes and distinguish between normal and neoplastic cells. Leukemic cells loss broad domains at T cell identity genes and gain broad domains at cancer-related genes. Moreover, the expression of genes, both coding and non-coding, associated with BH4D is frequently deregulated in T-ALL. Using an ex-vivo model we demonstrated that the ectopic expression of TLX3 oncogenic factor preferentially impact on the expression of BH4D-associated genes in T cell leukemia. Finally, an H3K4me3 demethylase inhibitor differentially targets T-ALL cell lines depending on the extend of the broad domains. Our results show that regulation of BH4D-associated genes is critical for leukemogenesis and suggest that association with BH4D might be used as epigenetic prioritization of cancer-relevant genes, including long non-coding RNAs

2021-04-16 | GSE151297 | GEO

Epigenomic translocation of H3K4me3 broad domains following super-enhancer hijacking

Project description:Epigenomic translocation of H3K4me3 broad domains following super-enhancer hijacking

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Broad H3K4me3 controls transcription output and timing during spermatid development

Project description:Male germ cells express a complex transcriptome under tight temporal regulation during their development. However, our knowledge of the epigenetic regulation of crucial stages in this process, such as meiotic onset, remains limited. Here, by dissecting a comprehensive map of the dynamic epigenomic landscape in developing mouse male germ cells, we uncover mutually exclusive shifts in the repressive histone marks H3K9me2, H3K9me3 and H3K27me3 during the mitosis-to-meiosis transition and completion of meiotic recombination. These dynamic shifts coincide with temporal changes in global transcriptional output, retrotransposon activity, and the silencing of mitotic/meiotic genes during spermatogenesis. In addition, we identify Setd1b-mediated broad H3K4me3 domains in both mouse and human spermatids. These broad H3K4me3 domains promote Pol II occupancy and transcription, resulting in high gene expression in spermatids. Setd1b ablation leads to a complete loss of broad H3K4me3, and the redistribution of Pol II from broad H3K4me3 promoters to regular H3K4me3 promoters, thereby compromising temporal gene expression and ultimately hampering spermiogenesis. These findings reveal that dynamic epigenetic changes orchestrate stage-specific gene expression in spermatogenesis, with Setd1b-mediated broad H3K4me3 serving as a crucial regulator that controls the timing of stage-specific gene expression in spermatids.

2024-09-03 | GSE242515 | GEO

Dynamics of broad H3K4me3 domains uncover an epigenetic switch between cell identity and cancer-related genes.

Project description:Broad domains of H3K4 methylation have been associated with consistent expression of tissue-specific, cell identity, and tumor suppressor genes. Here, we identified broad domain-associated genes in healthy human thymic T cell populations and a collection of T cell acute lymphoblastic leukemia (T-ALL) primary samples and cell lines. We found that broad domains are highly dynamic throughout T cell differentiation, and their varying breadth allows the distinction between normal and neoplastic cells. Although broad domains preferentially associate with cell identity and tumor suppressor genes in normal thymocytes, they flag key oncogenes in T-ALL samples. Moreover, the expression of broad domain-associated genes, both coding and noncoding, is frequently deregulated in T-ALL. Using two distinct leukemic models, we showed that the ectopic expression of T-ALL oncogenic transcription factor preferentially impacts the expression of broad domain-associated genes in preleukemic cells. Finally, an H3K4me3 demethylase inhibitor differentially targets T-ALL cell lines depending on the extent and number of broad domains. Our results show that the regulation of broad H3K4me3 domains is associated with leukemogenesis, and suggest that the presence of these structures might be used for epigenetic prioritization of cancer-relevant genes, including long noncoding RNAs.

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Broad H3K4me3 domains support oocyte genome silencing and maturation but are dispensable for repression in early embryos

Project description:To investigate whether demethylation of broad histone H3 lysine 4 trimethyl (H3K4me3) domains is sufficient to trigger premature embryonic genome activation (EGA), we overexpressed the H3K4me3 demethylase KDM5B in mouse zygotes and early 2-cell (2C) embryos via mRNA injection. We performed single-cell RNA sequencing (scRNA-seq) using the SMART-Seq Stranded Kit (Takara Bio) on individual Kdm5b-yfp–injected and water-injected control zygotes and 2C embryos. Differential expression analysis revealed minimal transcriptional changes, and developmental stage, rather than KDM5B overexpression, accounted for most gene expression variance. Our findings demonstrate that wide-scale removal of H3K4me3 in zygotes or early 2C embryos is not sufficient to induce premature EGA, suggesting that genome silencing at these stages does not depend on broad H3K4me3 domains.

2025-10-01 | GSE309712 | GEO

Epigenomic translocation of H3K4me3 broad domains following super-enhancer hijacking

Project description:Chromosomal translocations are important drivers of haematological malignancies whereby proto-oncogenes are activated by juxtaposition with super-enhancers, often called super-enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the enhancers of the immunoglobulin heavy chain locus (IGH) and proto-oncogene CCND1 that are common in B-cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterised the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B-cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of this locus. We observed similar cancer-specific H3K4me3-BDs associated with super-enhancer hijacking of other common oncogenes in B-cell (MAF, MYC and FGFR3) and in T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs are created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs accompanies the translocation of super-enhancers.

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Unique Broad Histone Lysine 4 Methylation Domains in Mouse Oocytes and Dynamic Regulation during Maternal to Zygotic Transition

Project description:The maternal to zygotic transition (MZT) involves the transfer of genome regulation from the oocyte to the embryo and is essential for the formation of totipotent embryos. However, regulatory mechanisms are still poorly understood despite recent progress in mapping the dynamics in RNA transcripts and DNA methylation1-9. Previous studies suggest that dynamic histone modifications may play important roles in MZT10-12, however direct measurements of chromatin states has been hindered by technical difficulties in profiling histone modifications from small quantities of cells. We have developed a micro-scale chromatin immunoprecipitation and sequencing (μChIP-seq) method and used it to profile histone H3 lysine methylation (H3K4me3) and acetylation (H3K27ac) genome-wide in the mouse oocyte, 2- cell and 8-cell stage embryo. Strikingly, we show that ~22% of the oocyte genome is associated with broad H3K4me3 domains that are anti-correlated with DNA methylation. Most H3K4me3 signal is rapidly lost and constricted to TSS regions in 2-cell embryos, concomitant with the onset of major zygotic genome activation (ZGA). We provide evidence that these broad H3K4me3 domains are established by Mll2 and actively removed by Kdm5a and Kdm5b, and likely play instrumental roles in MZT by defining regions of DNA demethylation in oocytes and the 2-cell embryo. Furthermore, broad H3K4me3 domains specify H3K27ac patterns in the early embryo and ZGA genes are generally related to broad H3K4me3 domains, suggesting a fundamental role in MZT. Our results provide insights into how the developmental program can be set up in the oocyte and transferred to the zygotic genome.

2016-09-08 | GSE72784 | GEO

Dynamic of broad H3K4me3 domains uncover an epigenetic switch between cell identity and cancer-related genes

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-04-16 | GSE164228 | GEO

Deciphering H3K4me3 Broad Domains Associated With Gene Regulatory Networks and Conserved Epigenomic Landscapes in the Human Brain

Project description:Deciphering H3K4me3 Broad Domains Associated With Gene Regulatory Networks and Conserved Epigenomic Landscapes in the Human Brain

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