Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers

Abstract

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.

High-resolution simulations of chromatin folding at genomic rearrangements in malignant B-cells provide mechanistic insights on proto-oncogene deregulation

“…The remodelling includes the appearance of an H3K4me3 broad domain over CCND1; the results here support our previous work suggesting that such broad domains are associated with super-enhancer hijacking [9]. Importantly, the chromosomal locations which are predicted by the model to strongly interact with CCND1 could be used for targeting in future experiments which aim to uncover the mechanisms through which broad domains are generated.…”

“…The 100 kbp inserted region in U266 includes E α 1 (accurately mapped in Ref. [9]). U266 is a highly useful model because it allows study of the effect of relocating a single IGH enhancer within an existing TAD; strikingly, it leads to significant changes in expression which are similar to those resulting from a reciprocal translocation.…”

“…Simulated Hi-C map from simulations of Z-138 cells which possess a t(11;14) translocation (hg19_z138 genome build). Positions of the previously identified IGH super-enhancers are shown as purple blocks above the map [9]. Simulation input data (DHS, chromatin states and CTCF peaks) are shown under the map as in previous figures.…”

“…IGH - CCND1 is a common translocation observed in mantle cell lymphoma (MCL) and multiple myeloma (MM); when translocated together the IGH super-enhancers drive CCND1 over-expression. In previous work [9] we analysed the changes in chromatin states associated with super-enhancer translocation events, finding that relocation of the IGH super-enhancer results in local chromatin remodelling and the emergence of patterns of histone modifications including H3K4me3 broad domains [9, 17, 18]. Here we study how these epigenetic changes alter 3D chromosome structure.…”

“…Simulations of an MM cell line where a single IGH super-enhancer is inserted into the CCND1 -TAD predicted that while the TAD remains intact, chromatin interactions among gene promoters and emergent regulatory regions are radically altered. Predictions for an MCL cell line possessing a translocation which repositions CCND1 next to the IGH joining region [16] showed an oncogenic fusion TAD encompassing CCND1 and four previously identified IGH super-enhancer regions [9, 20–22]. Further simulations suggest that it is the downstream epigenetic changes which drive the 3D changes, rather than the genomic rearrangements itself.…”