Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers
- Aneta Mikulasova1,
- Daniel Kent2,
- Marco Trevisan-Herraz1,
- Nefeli Karataraki2,
- Kent T.M Fung2,
- Cody Ashby3,
- Agata Cieslak4,
- Shmuel Yaccoby3,
- Frits van Rhee3,
- Maurizio Zangari3,
- Sharmilan Thanendrarajan3,
- Carolina Schinke3,
- Gareth J Morgan5,
- Vahid Asnafi4,
- Salvatore Spicuglia6,
- Chris A Brackley7,
- Anne E Corcoran8,
- Sophie Hambleton2,
- Brian A Walker9,
- Daniel Rico1 and
- Lisa J Russell2,10
- 1 Newcastle University, Biosciences Institute;
- 2 Newcastle University, Translational and Clinical Research Institute;
- 3 University of Arkansas for Medical Sciences;
- 4 Université de Paris, Institut Necker Enfants Malades;
- 5 NYU Langone Medical Center, Perlmutter Cancer Center;
- 6 Aix-Marseille University, INSERM;
- 7 University of Edinburgh;
- 8 Babraham Institute;
- 9 Indiana University, Melvin and Bren Simon Comprehensive Cancer Center
Abstract
Chromosomal translocations are important drivers of hematological malignancies whereby proto-oncogenes are activated by juxtaposition with super-enhancers, often called enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the super-enhancers of the immunoglobulin heavy 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 its gene body. We observed similar cancer-specific H3K4me3-BDs associated with super-enhancer hijacking of other common oncogenes in B cell (MAF, MYC and FGFR3/NSD2) and in T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs can be created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs from cell identity genes to oncogenes accompanies the translocation of super-enhancers.
- Received July 30, 2021.
- Accepted December 15, 2021.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International license), as described at http://creativecommons.org/licenses/by/4.0/.
