Virus-Human Chromatin Interactions Reorganise 3D Genome and Hijack KDM5B for Promoting Metastasis in Nasopharyngeal Carcinoma [CUT&RUN-seq]

As the first human DNA tumour virus Epstein-Barr virus (EBV) is detectable in over 90% of nasopharyngeal carcinoma (NPC) patients in the endemic regions. Genome-wide analysis of 3D chromosome conformation revealed the virus-host chromatin interactions induce spatial reorganisation of loops and compartments, exhibiting “enhancer infestation” and “H3K27 bivalency” at EBV interaction regions (EBVIRs). Through this mechanism, EBV hijacks KDM5B, a genome stability gatekeeper, and its binding targets leading to aberrant activation of the EBVIRs-enhancer-KDM5B signature. The cancer cells with this signature had increased MYC activation, DNA damage responses, and epigenetic plasticity for epithelial-immune cell dual features with metastatic potential. Our multi-centre multi-omics study further confirmed that this signature was highly relevant to chromosome instability and could be utilised as a risk factor for distant metastasis. This study highlights a novel paradigm where latent viral episomes could alter host high-order epigenotype, promoting transcriptional rewiring and risk of metastasis in NPC.