Integration of human papillomavirus (HPV) DNA into the human genome is a reputed key driver of cervical cancer. However, the effects of HPV integration on chromatin structural organization and gene expression are largely unknown. We studied a cohort of 61 samples and identified an integration hot spot in the CCDC106 gene on chromosome 19. We then selected fresh cancer tissue that contained the unique integration loci at CCDC106 with no HPV episomal DNA and performed whole-genome, RNA, chromatin immunoprecipitation and high-throughput chromosome conformation capture (Hi-C) sequencing to identify the mechanisms of HPV integration in cervical carcinogenesis. Molecular analyses indicated that chromosome 19 exhibited significant genomic variation and differential expression densities, with correlation found between three-dimensional (3D) structural change and gene expression. Importantly, HPV integration divided one topologically associated domain (TAD) into two smaller TADs and hijacked an enhancer from PEG3 to CCDC106, with a decrease in PEG3 expression and an increase in CCDC106 expression. This expression dysregulation was further confirmed using 10 samples from our cohort, which exhibited the same HPV-CCDC106 integration. In summary, we found that HPV-CCDC106 integration altered local chromosome architecture and hijacked an enhancer via 3D genome structure remodeling. Thus, this study provides insight into the 3D structural mechanism underlying HPV integration in cervical carcinogenesis.

将人乳头瘤病毒（HPV）DNA整合到人基因组中是宫颈癌的著名关键驱动力。但是，HPV整合对染色质结构组织和基因表达的影响尚不清楚。我们研究了一组61个样本，并确定了19号染色体上CCDC106基因的整合热点。然后，我们选择了包含CCDC106独特整合位点的新鲜癌组织。没有HPV游离DNA，并进行了全基因组，RNA，染色质免疫沉淀和高通量染色体构象捕获（Hi-C）测序，以鉴定HPV整合在宫颈癌变中的机制。分子分析表明，第19号染色体表现出显着的基因组变异和差异表达密度，在三维（3D）结构变化与基因表达之间具有相关性。重要的是，HPV整合划分一个拓扑学相关联的域（TAD）成两个较小的TAD的和劫持增强从PEG3到CCDC106，在降低PEG3表达和增加CCDC106表达。使用我们队列中的10个样本进一步证实了这种表达失调，这些样本表现出相同的HPV- CCDC106整合。总之，我们发现HPV- CCDC106整合改变了局部染色体的结构，并通过3D基因组结构重塑劫持了增强子。因此，本研究为宫颈癌发生中HPV整合的3D结构机理提供了见识。