Epigenomic translocation of H3K4me3 broad domains following super-enhancer hijacking

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. Myeloma cell lines KMS11 and MM1S were analysed using ChIP-seq of six histone marks (H3K4me1, H3K4me3, H3K9me3, H3K27me3, H3K27Ac, and H3K36me3) to study H3K4me3 broad domain at proto-oncogenes involved in genomic translocations. ChIP-seq data of T-cell acute lymphoblastic leukemia cell line PEER was used to observe changes in H3K4me3 and H3K27ac profiles at TAL1 locus after CRISPR-Cas9 editing that introduced upstream 12bp insertion known from Jurkat cell line.