Histone Modifications in Development and Malignancy

Non-Hodgkin lymphoma (NHL) development is driven by the accumulations of multiple genetic, epigenetic, and chromosomal alterations. These lesions can lead to modifications of the chromatin architecture. To identify novel oncogenic interactions driven by modifications of the chromatin 3D organization, we combined high-throughput chromatin conformation capture data (Hi-C) in lymphoma cells with whole genome sequencing (WGS) and epigenetic and transcriptional profiles of primary patient samples and cell lines. Recently, we found that a significant interplay exists between the compartmentalization of the genome into topologically associating domains (TADs) and epigenetic and transcriptional changes mediated by mutated EZH2. Indeed, EZH2 mutations drive aberrant increase of H3K27me3 within specific TADs, resulting in loss of promoter-promoter interactions, synergistic silencing of multiple tumor suppressors and, thus, increased B-cell proliferation and tumor aggressiveness¹. Now, we are further investigating how chromosomal amplifications and translocations forms new long-range interactions between enhancers and promoters to support oncogene expression. Importantly, we observed that epigenetic editing of enhancers and pharmacological depletion of H3K27Ac reduces the number of interactions between specific enhancers and promoters and this loss of interactions directly affects gene expression and cell differentiation. These results indicate that is possible to block the oncogenic effect of chromosomal alterations by targeting epigenetic modification in enhancer regions and preventing the formation of oncogenic chromatin interactions. Overall, our results demonstrate that it is important to contextualize the effects of genomic alterations in the 3D organization of the chromatin, to uncover new oncogenic mechanisms and improve the design of new therapeutic approaches.

1. Donaldson-Collier MC, Sungalee S, Zufferey M, et al. EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains. Nat Genet. 2019;51(3):517. doi:10.1038/s41588-018-0338-y