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

尽管目前有有效的预防性疫苗，但人乳头瘤病毒感染仍然是性病的最常见原因。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类乳头状瘤病毒的传播。这些病毒的生产性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编码蛋白质的mRNAs的作用上。然而，大多数细胞转录组并不编码蛋白质。一些非编码RNA可能代表功能无关的转录噪声，但有几类非编码RNA具有重要的调节功能。直到最近，长的非编码RNA才成为许多细胞调节电路的关键调节器。人乳头状瘤病毒复制其基因组以高拷贝数，并在终末分化的上皮细胞中产生后代病毒。我们发现，在上皮分化过程中，长非编码RNA Dino的表达增加，并且在患者来源的含有人乳头瘤病毒Episome的细胞系中，长非编码RNA Dino的异位表达导致病毒基因组的增加。这一建议解决了这样的假设，即Dino在调节人乳头状瘤病毒分化依赖的生命周期方面发挥了以前没有预料到的作用。我们将采用生化、细胞和分子生物学的组合方法来确定Dino在人类乳头瘤病毒基因组复制中的生物学活性，这些细胞系包括EB病毒在内的患者来源的分裂和分化的病毒。我们的研究结果将对人乳头瘤病毒依赖分化的生命周期产生新的分子见解。

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.