Every human cell packs two metres of DNA into a nucleus a millionth of a metre across, and the way that DNA is twisted and folded controls which genes are switched on or off. The researchers have developed a new method to map these twists—called topological domains—across the entire human genome. They want to understand how over-wound and under-wound DNA regions influence gene activity, DNA copying, and chromosome stability. This matters because in many cancers, certain genome regions become fragile and prone to breaking, which is an early step in tumour development. The team will identify what makes these fragile regions unstable and how DNA topology contributes to that instability. If successful, this fundamental science could reveal the mechanistic basis for many chromosomal abnormalities. While there is no immediate practical application, understanding how genome architecture drives instability may eventually help detect early cancerous changes or suggest new ways to reduce the likelihood of cancer growth. Past discoveries in genome organisation have already reshaped how we understand gene regulation and disease.
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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.
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