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Browsing by Author "Yaccoby, Shmuel"
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Item Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers(CSH Press, 2021-12) Mikulasova, Aneta; Kent, Daniel; Trevisan-Herraz, Marco; Karataraki, Nefeli; Fung, Kent T. M.; Ashby, Cody; Cieslak, Agata; Yaccoby, Shmuel; Rhee, Frits van; Zangari, Maurizio; Thanendrarajan, Sharmilan; Schinke, Carolina; Morgan, Gareth J.; Asnafi, Vahid; Spicuglia, Salvatore; Brackley, Chris A.; Corcoran, Anne E.; Hambleton, Sophie; Walker, Brian A.; Rico, Daniel; Russell, Lisa J.; Medicine, School of MedicineChromosomal 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.Item PHF19 inhibition as a therapeutic target in Multiple Myeloma(Elsevier, 2021) Schinke, Carolina D.; Bird, Jordan T.; Qu, Pingping; Yaccoby, Shmuel; Lyzogubov, Valeriy V.; Shelton, Randal; Ling, Wen; Boyle, Eileen M.; Deshpande, Sharyu; Byrum, Stephanie D.; Washam, Charity; Mackintosh, Samuel; Stephens, Owen; Thanendrarajan, Sharmilan; Zangari, Maurizio; Shaughnessy, John, Jr.; Zhan, Fenghuang; Barlogie, Bart; van Rhee, Frits; Walker, Brian A.; Medicine, School of MedicineEpigenetic deregulation is increasingly recognized as a contributing pathological factor in multiple myeloma (MM). In particular tri-methylation of H3 lysine 27 (H3K27me3), which is catalyzed by PHD finger protein 19 (PHF19), a subunit of the Polycomb Repressive Complex 2 (PRC2), has recently shown to be a crucial mediator of MM tumorigenicity. Overexpression of PHF19 in MM has been associated with worse clinical outcome. Yet, while there is mounting evidence that PHF19 overexpression plays a crucial role in MM carcinogenesis downstream mechanisms remain to be elucidated. In the current study we use a functional knock down (KD) of PHF19 to investigate the biological role of PHF19 and show that PHF19KD leads to decreased tumor growth in vitro and in vivo. Expression of major cancer players such as bcl2, myc and EGR1 were decreased upon PHF19KD further underscoring the role of PHF19 in MM biology. Additionally, our results highlighted the prognostic impact of PHF19 overexpression, which was significantly associated with worse survival. Overall, our study underscores the premise that targeting the PHF19-PRC2 complex would open up avenues for novel MM therapies.