HPV16 oncogene expression levels during early cervical carcinogenesis are determined by the balance of epigenetic chromatin modifications at the integrated virus genome

摘要: In cervical squamous cell carcinomas, high-risk human papillomavirus (HRHPV) DNA is usually integrated into host chromosomes. Multiple integration events are thought to be present within the cells of a polyclonal premalignant lesion and features that underpin clonal selection one particular integrant remain poorly understood. We previously used W12 model system generate panel keratinocyte clones, derived from low-grade naturally infected with major HRHPV type, HPV16. The were isolated regardless their selective advantage differed only by site HPV16 genome. this resource test hypothesis levels E6/E7 oncogene expression in regulated epigenetically. performed comprehensive analysis epigenetic landscape selected which virus per template varied ~6.6-fold. Across examined, higher associated more open chromatin at long control region, together greater loading remodelling enzymes lower nucleosome occupancy. There histone post-translational modification hallmarks transcriptionally active repressive hallmarks. was abundance active/elongating form RNA polymerase-II enzyme (RNAPII-Ser2P), CDK9, component positive transcription elongation factor b complex responsible for Ser2 phosphorylation. changes observed functionally significant, as showed sensitivity depletion and/or inhibition acetyltransferases CDK9 less deacetylase inhibition. conclude gene following determined through multiple layers regulation, likely contribute individual during carcinogenesis.