"Epigenetics describes the modification of gene expression without changing the DNA sequence. It is now well established that epigenetics plays a major role in cancer development. The Clark lab in which Dr. Coolen currently works (Sydney, Australia), has discovered that such epigenetic changes in cancer are not always localised to individual genes, but can encompass large chromosomal regions resulting in silencing of neighbouring genes (“Long Range Epigenetic Silencing” or LRES). They have now established that LRES commonly occurs in cancer and have identified 47 new LRES regions in prostate cancer (Coolen et al submitted). In collaboration with my lab in Nijmegen, the Netherlands, we are now in a world-leading position to unravel the critical components of this novel epigenetic control pathway in carcinogenesis. In particular, with our expertise on next generation sequencing technology we can address in detail the role of non-coding RNA in directing chromatin-remodelling across LRES regions. The expected results arising from this proposed study include characterisation of a new mechanism of gene inactivation through RNA-directed epigenetic remodelling. OVERALL AIM: In this proposal we aim to delineate the mechanism of RNA-directed epigenetic remodelling. HYPOTHESIS: Non-coding RNA transcripts can direct chromatin remodelling enzymes to target regions in the genome, thereby triggering specific genes or regions in the genome that become repressed. In cancer, chromatin remodelling non-coding RNA transcripts are deregulated leading to gene suppression and epigenetic remodelling. SPECIFIC AIMS: 1. To identify and characterise RNA transcripts bound to the H3K9 and H3K27 methyltransferase enzymes, G9a and EZH2, in normal and cancer cells. 2. To identify the epigenetic fate of regions targeted by the HMT-RNA complexes. 3. To manipulate levels of HMT-RNA complexes and interrogate their role in chromatin remodelling."