Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers
Author(s) -
Aneta Mikulášová,
Daniel Kent,
Marco Trevisán-Herraz,
Nefeli Karataraki,
Kent Fung,
Cody Ashby,
Agata Cieślak,
Shmuel Yaccoby,
Frits van Rhee,
Maurizio Zangari,
Sharmilan Thanendrarajan,
Carolina Schinke,
Gareth J. Morgan,
Vahid Asnafi,
Salvatore Spicuglia,
Chris A. Brackley,
Anne E. Corcoran,
Sophie Hambleton,
Brian A. Walker,
Daniel Rico,
Lisa J. Russell
Publication year - 2021
Publication title -
genome research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.556
H-Index - 297
eISSN - 1549-5469
pISSN - 1088-9051
DOI - 10.1101/gr.276042.121
Subject(s) - epigenomics , biology , h3k4me3 , enhancer , chromatin , genetics , chromosomal translocation , locus (genetics) , epigenetics , breakpoint , dna methylation , cancer research , gene , gene expression , promoter
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.
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