Epigenomic translocation of H3K4me3 broad domains following super-enhancer hijacking
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA636364 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11901986.fastq.gz | Fastqsanger.gz | |||
| SRR11901987.fastq.gz | Fastqsanger.gz | |||
| SRR11901988.fastq.gz | Fastqsanger.gz | |||
| SRR11901989.fastq.gz | Fastqsanger.gz | |||
| SRR11901990.fastq.gz | Fastqsanger.gz |
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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.
2020-08-12 | GSE151556 | GEO
Project description:Chromosomal translocations are important drivers of haematological malignancies whereby proto-oncogenes are activated by juxtaposition with super-enhancers, often called enhancer hijacking. To examine this phenomenon we used ChipSeq based on a combination of six histone modifications as follows: H3K4me1, H3K4me3, H3K9me3, H3K27me3, H3K27Ac and H3K36me3. Samples are patient-derived xenografts generated by passaging primary patient CD138+ selected cells through the SCID-rab myeloma mouse model.
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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
Project description:Stretched histone regions, such as super-enhancers and broad H3K4me3 domains, are associated with maintenance of cell identity and cancer. We connected super-enhancers and broad H3K4me3 domains in the K562 chronic myelogenous leukemia cell line as well as the MCF-7 breast cancer cell line with chromatin interactions. Super-enhancers and broad H3K4me3 domains showed higher association with chromatin interactions than their typical counterparts. Interestingly, we identified a subset of super-enhancers that overlap with broad H3K4me3 domains and show high association with cancer-associated genes including tumor suppressor genes. Besides cell lines, we could observe chromatin interactions by a Chromosome Conformation Capture (3C)-based method, in primary human samples. Several chromatin interactions involving super-enhancers and broad H3K4me3 domains are constitutive and can be found in both cancer and normal samples. Taken together, these results reveal a new layer of complexity in gene regulation by super-enhancers and broad H3K4me3 domains.
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Project description:Super-enhancers (SEs) and broad H3K4me3 domains (BDs) are crucial regulators in the control of tissue identity in human and mouse. However, their features in pig remain largely unknown. In this study, by integrative computational analyses of epigenomic and transcriptomic data, we have characterized SEs and BDs in six pig tissues and analyzed their conservation in comparison with human and mouse tissues. Similar to human and mouse, pig SEs and BDs display higher tissue specificity than their typical counterparts. Genes proximal to SEs and BDs are associated with tissue identity in most tissues. About 55-182 SEs (5-17% in total) and 99-309 BDs (8-16% in total) across pig tissues are considered as functionally conserved elements because they have orthologous SEs and BDs in human and mouse. However, these elements do not necessarily exhibit sequence conservation. The functionally conserved SEs are correlated to tissue identity in majority of pig tissues, while those conserved BDs are linked to tissue identity in a few tissues. Our study provides resources for future gene regulatory studies in pig. It highlights that SEs are more effective in defining tissue identity than BDs, which is contrasting to a previous study. It also provides novel insights on understanding the sequence features of functionally conserved elements.
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Project description:Broad domain promoters and super enhancers are regulatory elements that govern cell-specific functions and harbor disease-associated sequence variants. These elements are characterized by distinct epigenomic profiles, such as expanded deposition of histone marks H3K27ac for super enhancers and H3K4me3 for broad domains, however little is known about how they interact with each other and the rest of the genome in three-dimensional chromatin space. Using network theory methods, we studied chromatin interactions between broad domains and super enhancers in three ENCODE cell lines (K562, MCF7, GM12878) obtained via ChIA-PET, Hi-C, and Hi-CHIP assays. In these networks, broad domains and super enhancers interact more frequently with each other compared to their typical counterparts. Network measures and graphlets revealed distinct connectivity patterns associated with these regulatory elements that are robust across cell types and alternative assays. Machine learning models showed that these connectivity patterns could effectively discriminate broad domains from typical promoters and super enhancers from typical enhancers. Finally, targets of broad domains in these networks were enriched in disease-causing SNPs of cognate cell types. Taken together these results suggest a robust and unique organization of the chromatin around broad domains and super enhancers: loci critical for pathologies and cell-specific functions.
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Project description:Clusters of enhancers called super-enhancers are associated with gene activation. Broad trimethyl histone H3 lysine 4 (H3K4me3) often defines actively transcribed tumor suppressor genes. However, how these epigenetic signatures are regulated for tumor suppression is poorly understood. Here, we show that brain-specific knockout of the H3K4 methyltransferase MLL4 (aka KMT2D) in mice spontaneously induces cerebellar tumors in brain while indirectly increasing expression of oncogenic programs, such as Ras activators and Notch pathway components. Mll4 loss caused widespread impairment of super-enhancers and broad H3K4me3. Notably, Mll4 loss reduced super-enhancer and broad H3K4me3 signals in tumor suppressor genes co-marked by both signatures, including Dnmt3a and Bcl6. MLL4 upregulates DNMT3A-mediated DNA methylation to downregulate expression of Ras activators and increases Bcl6 expression to suppress the Notch pathway. These findings suggest an unanticipated epigenetic tumor-suppressive mechanism in which MLL4 is required for establishing super-enhancers and broad H3K4me3 for anti-tumor programs in normal cells.
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Project description:Broad chromosomal domains of histone modification patterns in C. elegans
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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
Project description:Dynamic of H3K4me3-broad domains uncover an epigenetic switch between cell identity and cancer-related genes
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