Epigenetic regulation of gene expression by the exoribonuclease pacman

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Development of an organism from egg to adult requires sets of genes to be switched on and off at particular times and in the correct order. If genes are not switched off when necessary, cells can continue to multiply in an uncontrolled way leading to cancer. As well as being important in cancer, gene regulation is crucial in controlling the balance between stem cell self-renewal and pathways to cell specialisation which are required to form the particular cells and tissues in the body. Since stem cells have a vast potential in regenerative medicine for the replacement of defective tissue, the understanding of gene control is crucial for harnessing the potential of these cells. Therefore studying the mechanisms whereby genes are switched off (as well as on) is vitally important for providing basic knowledge that has potential to lead to novel therapeutics. Using the fruit fly Drosophila as a model organism, we have recently discovered that an enzyme named Pacman is involved in the growth and differentiation of imaginal discs, which form adult structures such as wings and legs. Imaginal discs are similar to stem cells in that they carry the information to build the adult tissue. We have shown that Pacman normally affects the production of a protein called Simjang (Korean for 'strong heart') which in turn controls a gene silencing complex (the NuRD complex) which shuts down parts of the chromosome, preventing genes from being turned on. This gene silencing complex is important because it is known to be involved in many critical cellular events including tissue regeneration, formation of blood cells, ageing and spread of cancer cells. This is the first time that an enzyme involved in degradation of messenger RNA has been shown to be directly affecting a gene silencing complex. The aim of this project is to understand how the Pacman uses Simjang to control particular sets of genes involved in growth and differentiation. Our hypothesis is that, in normal cells, simjang messenger RNA is somehow 'tagged' for destruction so that not much of Simjang protein is made. This means that there is not enough Simjang to turn on the gene silencing complexes. These gene silencing complexes, when activated, normally act as 'brakes' to prevent growth and differentiation of the wing disc. Therefore when the brake is not pressed by Simjang, these genes are not turned on, allowing normal growth and development of the tissue. When the pacman gene is mutated, there is no (or little) degradation of simjang RNA, resulting in more Simjang protein, which turns on the gene silencing complexes (i.e. presses the brake) therefore switching on genes that prevent tissue growth and development. In this project we aim to test this hypothesis, find out the details of this gene control pathway and identify the genes which act as brakes to prevent growth and development. The mechanism of gene regulation which forms the basis of this proposal is entirely novel; as yet no research group has found this link between RNA degradation and gene silencing. Since all the proteins involved are similar in Drosophila and humans the new 'control module' we have discovered is likely to be relevant to gene regulation in humans. Since Pacman is known to be important in other important cellular events such as wound healing, migration of cell sheets, and male fertility, this work may also shed light on the molecular mechanisms of these processes in other tissues. Therefore the insights we gain during this project may help us to improve treatment for cancer and other diseases and also help us to understand the ways that tissues grow and develop. This project will therefore provide valuable insights into a new method of gene regulation which can be used in the development of new therapeutics.