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Epigenomic translocation of H3K4me3 broad domains following super-enhancer hijacking

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

PROVIDER: PRJNA636364 | ENA |

REPOSITORIES: ENA

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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.

2020-08-12 | GSE151556 | GEO

MM samples for 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 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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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

Super-Enhancers and Broad H3K4me3 Domains Form Complex Gene Regulatory Circuits Involving Chromatin Interactions.

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Chromatin interaction networks revealed unique connectivity patterns of broad H3K4me3 domains and super enhancers in 3D chromatin.

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MLL4 establishes super-enhancers and broad H3K4me3 for tumor-suppressive function

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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