Final Report Summary - FUNCTIONALEDGE (Determining the roles of the nuclear periphery in mammalian genome function)
DNA sequence and epigenetic chromatin maps are important in our understanding of how genomes are regulated. However, these maps are linear and do not account for the three-dimensional context within which the genome functions in the cell. The spatial organisation of the genome in the nucleus is not random – inactive regions of the genome tend to be found at the edge of the nucleus. This project aimed to determine the factors influencing how and why specific genes are located at the edge of the nucleus and how this might be altered during development and in disease.
Several genes move away from the nuclear periphery as they are activated during the differentiation of stem cells but by simply observing these changes it has been hard to establish cause or consequence – i.e. to genes move away from the periphery in order to be switched on, or do they move because they are switched on. By developing new synthetic biology tools to experimentally manipulate either gene expression or chromatin structure we have been able to definitively show that remodelling chromatin structure is enough to relocate a gene away from the edge of the nucleus. Surprisingly, we have found that this ‘new’ nuclear position is ‘remembered’ in subsequent cell generation – a so called epigenetic memory.
The project also revealed altered nuclear organisation in cancer, and in development, and was involved in identifying proteins that can affect nuclear organisation. Evidence was also obtained indicating that altered proteins at the edge of the nucleus, found in a disease of premature aging, can affect the ability of cells to respond to oxidative stress. The project also developed new tools ‘DNA oligo paints’ that allow specific classes of DNA sequence to be visualised in cells ‘en masse’ rather than gene by gene.
Several genes move away from the nuclear periphery as they are activated during the differentiation of stem cells but by simply observing these changes it has been hard to establish cause or consequence – i.e. to genes move away from the periphery in order to be switched on, or do they move because they are switched on. By developing new synthetic biology tools to experimentally manipulate either gene expression or chromatin structure we have been able to definitively show that remodelling chromatin structure is enough to relocate a gene away from the edge of the nucleus. Surprisingly, we have found that this ‘new’ nuclear position is ‘remembered’ in subsequent cell generation – a so called epigenetic memory.
The project also revealed altered nuclear organisation in cancer, and in development, and was involved in identifying proteins that can affect nuclear organisation. Evidence was also obtained indicating that altered proteins at the edge of the nucleus, found in a disease of premature aging, can affect the ability of cells to respond to oxidative stress. The project also developed new tools ‘DNA oligo paints’ that allow specific classes of DNA sequence to be visualised in cells ‘en masse’ rather than gene by gene.