Understanding the regulation and topological organisation of DNA in the human genome

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In every mammalian cell DNA is packaged into chromatin, a massive nucleoprotein complex. As fundamental nuclear processes such as gene transcription, replication and repair occur in this environment it is important for us to understand chromatin and genome architecture. We have recently developed an assay for mapping high resolution DNA topology (folding) and have discovered that DNA in cells is organised into DNA "topological domains" consisting of over and under wound DNA. In this proposal we plan to investigate these topological domains across the human genome and investigate how they influence gene expression programmes, DNA replication and chromosome stability. In many human diseases including cancer the genome becomes fragile and certain regions of the genome have a propensity to becoming unstable. We will investigate the DNA topology and chromatin organisation of these fragile regions and identify the factors that make them unstable. Our research will enable us to characterise the mechanistic basis for many chromosomal aberrations and identify approaches that can be use to reduce the likelihood of genome instability. One of the first steps in cancer is the acquisition of genome instability. Characterising this process, will better enable us to comprehend the factors and mechanism involved and may in future enable us to either better detect early changes in cancer or develop new approaches for reducing the likelihood of cancer growth.