Regulation of the Human Papillomavirus Life Cycle by the Long Noncoding RNA DINO

尽管目前已有有效的预防性疫苗，但人乳头瘤病毒感染仍然是性病最常见的原因。人乳头瘤病毒相关疾病在医疗服务不足的人群中特别普遍。尽管进行了数十年的研究，但没有任何策略可以限制人乳头状瘤病毒的传播。这些病毒的生产性病毒生命周期已被广泛研究，但研究几乎完全集中在病毒和细胞蛋白以及蛋白编码mRNA的贡献上。然而，大多数细胞转录组不编码蛋白质。一些非编码RNA可能代表功能上不相关的转录噪音，但几类非编码RNA具有重要的调节功能。长的非编码RNA只是最近才出现作为许多细胞调节回路的关键调节剂。人乳头瘤病毒复制其基因组到高拷贝数，并在终末分化的上皮细胞中产生子代病毒。我们发现，长的非编码RNA DINO的表达在上皮分化过程中增加，并且长的非编码RNA DINO在患者来源的含有人乳头瘤病毒附加体的细胞系中的异位表达导致病毒基因组的增加。该提案解决了DINO在调节人乳头瘤病毒的分化依赖性生命周期方面发挥着以前未预料到的作用的假设。我们将部署生物化学，细胞和分子生物学方法的组合，以确定DINO在分裂和分化的含病毒游离体的患者源性细胞系中人乳头瘤病毒基因组复制中的生物活性。我们的研究结果将为人类乳头瘤病毒的分化依赖性生命周期提供新的分子见解。

Despite the currently available effective prophylactic vaccines, human papilloma virus infections remain the most common cause of venereal disease. Human papilloma virus-associated diseases are particularly prevalent in medically underserved segments of the population. Despite decades of research, there are no strategies that can limit the spread of human papilloma viruses. The productive viral life cycle of these viruses has been studied extensively, but research has almost exclusively focused on the contributions of viral and cellular proteins and protein-coding mRNAs. However, most of the cellular transcriptome does not encode proteins. Some non-coding RNAs likely represent functionally irrelevant transcriptional noise but several classes of non-coding RNAs serve important regulatory functions. Long non-coding RNAs have only recently emerged as critical modulators of many cellular regulatory circuits. Human papilloma viruses replicate their genomes to high copy numbers and generate progeny virus in terminally differentiated epithelial cells. We showed that expression of the long non-coding RNA DINO increases during epithelial differentiation and that ectopic expression of the long noncoding RNA DINO in a patient-derived, human papillomavirus episome- containing cell line causes an increase in viral genomes. This proposal addresses the hypothesis that DINO plays a previously unanticipated role in regulating the differentiation-dependent life cycle of human papillomaviruses. We will deploy a combination of biochemical, cell and molecular biology approaches to define the biological activities of DINO in human papillomavirus genome replication in dividing and differentiated viral episome-containing, patient-derived cell lines. The results from our studies will yield novel molecular insights into the differentiation-dependent life cycle of human papillomaviruses.