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

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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.