Christiansen Irene Kraus, Sandve Geir Kjetil, Schmitz Martina, Dürst Matthias, Hovig Eivind
Department of Microbiology and Infection Control, Akershus University Hospital, Lørenskog, Norway.
Department of Informatics, University of Oslo, Oslo, Norway.
PLoS One. 2015 Mar 20;10(3):e0119566. doi: 10.1371/journal.pone.0119566. eCollection 2015.
Integration of human papillomavirus (HPV) into the host genome is regarded as a determining event in cervical carcinogenesis. However, the exact mechanism for integration, and the role of integration in stimulating cancer progression, is not fully characterized. Although integration sites are reported to appear randomly distributed over all chromosomes, fragile sites, translocation break points and transcriptionally active regions have all been suggested as being preferred sites for integration. In addition, more recent studies have reported integration events occurring within or surrounding essential cancer-related genes, raising the question whether these may reflect key events in the molecular genesis of HPV induced carcinomas. In a search for possible common denominators of the integration sites, we utilized the chromosomal coordinates of 121 viral-cellular fusion transcripts, and examined for statistical overrepresentation of integration sites with various features of ENCODE chromatin information data, using the Genomic HyperBrowser. We find that integration sites coincide with DNA that is transcriptionally active in mucosal epithelium, as judged by the relationship of integration sites to DNase hypersensitivity and H3K4me3 methylation data. Finding an association between integration and transcription is highly informative with regard to the spatio-temporal characteristics of the integration process. These results suggest that integration is an early event in carcinogenesis, more than a late product of chromosomal instability. If the viral integrations were more likely to occur in destabilized regions of the DNA, a completely random distribution of the integration sites would be expected. As a by-product of integration in actively transcribing DNA, a tendency of integration in or close to genes is likely to be observed. This increases the possibility of viral signals to modulate the expression of these genes, potentially contributing to the progression towards cancer.
人乳头瘤病毒（HPV）整合到宿主基因组被视为宫颈癌发生过程中的决定性事件。然而，整合的确切机制以及整合在刺激癌症进展中的作用尚未完全明确。尽管据报道整合位点随机分布于所有染色体上，但脆性位点、易位断点和转录活跃区域均被认为是整合的优先位点。此外，最近的研究报道了在重要癌症相关基因内部或周围发生的整合事件，这引发了一个问题，即这些是否可能反映了HPV诱导的癌症分子发生过程中的关键事件。为了寻找整合位点可能的共同特征，我们利用了121个病毒 - 细胞融合转录本的染色体坐标，并使用基因组超级浏览器，根据ENCODE染色质信息数据的各种特征，对整合位点的统计过度代表性进行了检测。我们发现，根据整合位点与DNase超敏反应和H3K4me3甲基化数据的关系判断，整合位点与在黏膜上皮中转录活跃的DNA相吻合。发现整合与转录之间的关联对于整合过程的时空特征具有重要意义。这些结果表明，整合是癌症发生过程中的早期事件，而非染色体不稳定的晚期产物。如果病毒整合更有可能发生在DNA的不稳定区域，那么预计整合位点会完全随机分布。作为在活跃转录的DNA中整合的副产物，可能会观察到整合在基因内部或附近的趋势。这增加了病毒信号调节这些基因表达的可能性，可能有助于癌症的进展。
