The adenovirus oncoprotein E1B-55K reshapes epigenetic histone modifications in primary human cells

Oncogenic viruses can induce epigenetic changes in host cells, which may contribute to cell transformation and tumorigenesis by altering gene expression patterns. Human adenoviruses, while primarily known for their lytic infections, have also been implicated in oncogenic transformation in experimental settings, but the mechanisms underlying adenovirus oncoprotein-induced epigenetic dysregulation remain poorly defined. Building on our recent findings that the adenoviral oncoprotein E1B-55K coordinates cellular transformation through interactions with DNA-bound host transcription factors, we next sought to determine whether these interactions also influence the chromatin landscape. For this purpose, we investigated the epigenetic consequences of E1B-55K expression in primary human mesenchymal stromal cells using histone-targeting MNase chromatin immunoprecipitation-seq, complemented by RNA-seq analysis. We demonstrate that stable expression of HAdV-C5 E1B-55K leads to widespread changes in histone post-translational modifications across the genome. Most notably, E1B-55K expression results in a marked loss of the activating histone marks H3K4me3 and H3K27ac at specific promoters and enhancers. These epigenetic alterations correspond with significant changes in gene expression, suggesting that E1B-55K interferes with normal transcriptional programming by altering the establishment of key histone modifications. Our findings help explain how E1B-55K drives viral transformation by changing epigenetic patterns and improving our understanding of virus-host interactions at the chromatin level. By describing how human adenoviruses disrupt epigenetic homeostasis, we provide insights into the mechanisms by which oncogenic viruses promote early events in cellular transformation.IMPORTANCEOncogenic viruses can reshape host cell epigenomes to promote transformation, yet the mechanisms by which adenoviral oncogenes exert such control remain poorly understood. Here, we reveal that the human adenovirus E1B-55K oncoprotein induces widespread loss of activating histone modifications, leading to transcriptional silencing of key cellular genes in primary human cells. Building on our previous demonstration of efficient adenoviral transformation of primary human mesenchymal stromal cells, this study provides the first comprehensive view of E1B-55K-mediated epigenetic reprogramming. Our findings uncover a link between E1B-55K-host transcription factor interactions and chromatin remodeling, offering new insight into how adenoviruses disrupt epigenetic homeostasis to initiate early events in oncogenic transformation. These results provide direct evidence for the transcriptional repression function long postulated for E1B-55K and advance understanding of virus-host interplay at the chromatin level.