Defining the cistrome and quantitative transcriptome of virus-transformed cells using massively parallel sequencing

和人类一样，包括鸡在内的许多动物也会患上癌症。然而，与人类不同的是，鸡的大多数癌症是由病毒引起的。马立克氏病（MD）是鸡的一种常见病，包括瘫痪和因高度恶性T淋巴瘤（白细胞癌）的生长而死亡。MD是由一种传染性病原体马立克氏病病毒（MDV）引起的。MDV具有很强的传染性，是全世界家禽业的主要威胁。据估计，全世界因这种疾病造成的总损失高达20亿英镑。目前，它是通过接种疫苗来控制的，为了控制这种疾病，每年使用近220亿剂疫苗。尽管广泛接种疫苗，但这种疾病的威胁正在增加，需要进行更基础的研究，了解这种病毒导致癌症的机制，以制定更有效的控制规划。另一种在英国不太常见的鸡致癌病毒，网状内皮增生病毒（REV）是一种很好的癌症模型。利用这种病毒研究癌症机制的优点是，可以在从鸟类身上收集的鸡细胞上进行诱导癌症的实验。我们使用了这个模型，并检测了细胞转化为癌细胞时的分子变化。我们已经确定了正常癌细胞之间基因和小的22核苷酸microRNAs分子表达的非常重要的变化，表明这些变化有助于癌症的发生。在这项由动物健康研究所（康普顿）和ARK-Genomics（罗斯林研究所）联合进行的新拨款申请中，我们希望扩展这些研究，利用新的RNA-Seq技术获得基因表达变化的详细信息，该技术将提供更详细的基因表达的全面图片在转化过程中。同样，我们还将研究基因组中的序列，在这些序列中，病毒癌蛋白可以直接与DNA结合，改变基因表达，从而导致癌症。我们的目标是利用这个优秀的模型系统和Marek病癌症模型，获得详细的基因表达数据，了解和预测癌症的分子途径。这项研究对了解这些病毒诱发癌症的机制非常重要，其中一些对了解包括人类在内的其他物种的癌症很有价值。最后，该项目的研究结果将在开发控制由致瘤病毒引起的癌症的新方法方面非常有价值。

As in humans, many animals including chickens, develop cancer. However, unlike in humans, most of the cancers in chickens are caused by viruses. Marek's disease (MD) is a common disease of chickens involving paralysis and commonly death from the growth of highly malignant T lymphomas (cancers of white blood cells). MD is caused by a transmissible agent, Marek's disease virus (MDV). MDV is very contagious and is a major threat to the poultry industry worldwide. The estimated total loss from this disease worldwide is up to £ 2 billion. Presently, it is controlled by vaccination, and nearly 22 billion vaccine doses a year are used in an attempt to control the disease. Despite widespread vaccination, the threat from this disease is on the increase, and more fundamental studies to understand the mechanisms by which this virus cause cancer is needed to develop more effective control programmes. Another cancer inducing virus of chickens less common in the UK called Reticuloendotheliosis virus (REV) is a very good model for cancer. The advantage of using this virus for studying the mechanisms of cancer is that the experiments to induce cancer can be done on chicken cells collected from birds. We have used this model and examined the molecular changes to the cells while it is transformed into cancer cells. We have identified very important changes in the expression of genes and small 22-nucleotide microRNAs molecules between normal cancer cells, suggesting that these changes contribute to cancer. In this new grant proposal, to be carried out jointly between the Institute for Animal Health (Compton) and ARK-Genomics (Roslin Institute), we want to extend these studies to obtain detailed information on the changes in the expression of genes using the new RNA-Seq technology that will provide a much detailed comprehensive picture on the expression of genes during the transformation process. Similarly, we will also examine the sequences in the genomes where viral oncoproteins can directly bind to the DNA to change the gene expression to cause cancer. We aim to use this excellent model system and Marek's disease cancer model to obtain detailed gene expression data to understand and predict the molecular pathways to cancer. The study is very important to understand the mechanisms by which these viruses induce cancer, some of which are valuable in understanding cancer in other species including humans. Finally, the findings from the project will be very valuable in developing new approaches for the control of cancers caused by oncogenic viruses.