SRP309766 PRJNA707506 GSE168470 Histone acetylation dynamics modulate chromatin conformation and allele-specific interactions at oncogenic loci (Hi-C) In cancer cells, enhancer hijacking mediated by chromosomal alterations and/or increase of histone H3 lysine 27 acetylation (H3K27ac) can support oncogene expression. However, how the chromatin conformation of enhancer-promoter interactions is affected by these events is unclear. Here, by comparing chromatin structure and H3K27ac levels in normal and lymphoma B-cells, we show that enhancer-promoter interacting regions assume different conformations according to the local abundance of H3K27ac. Genetic or pharmacologic depletion of H3K27ac decreases the frequency and the spreading of these interactions, altering oncogene expression. Moreover, enhancer hijacking mediated by chromosomal translocations influences the epigenetic status of the regions flanking the breakpoint, prompting the formation of distinct intra-chromosomal interactions in the two homologous chromosomes. These interactions are accompanied by allele-specific gene expression changes. Overall, our work indicates that H3K27ac dynamics modulate interaction frequency between regulatory regions and can lead to allele-specific chromatin configurations to sustain oncogene expression. Overall design: 6 different samples and for each sample the number of replicates were based in sample availability and sequencig depth GSE168470 pubmed 33972799 parent_bioproject PRJNA707503