Role of CIZ1 in maintenance of epigenetic landscape in primary differentiated cells

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Cells in a developing embryo have the capability to become all of the different types of cell in the adult body. As they specialize they gradually turn off genes that are not required, until they only produce products that are essential to their function. One of the ways that their choice is restricted is by modification of specific proteins that are closely associated with the genes to be shut down. Once established, these modifications, or marks, must be copied each time a cell divides so that daughter cells have the same marks as their parents, and therefore access the same repertoire of genes as their parents. We are studying the mechanism that ensures marks are faithfully copied; the 'quality control' process that stops a cell from drifting away from its chosen path.Specifically, we are interested in how the chosen genes and the proteins that add the marks (factors) find each other among the mass of DNA packed into the cell nucleus. Do the factors diffuse around the nucleus until they happen to come across the correct genes, or is there a delivery system that ensures 'letters' reach the right 'address' in good time? Our experiments will look at whether, in normal cells, the factors are confined to factory sites, restricting their ability to diffuse around. This would mean that genes must visit factories to be marked, which could afford tight control over the process. So far, there has been very little investigation of this because (our data suggest) restriction to factories appears to be absent or overridden in most of the cell types that are commonly used by researchers (stem cells, cancer cells, cultured cells). In order to understand whether restriction to factories is the norm for non-diseased cells in the body, it is necessary to work with newly isolated cells that have not been adapted to long-term growth in a laboratory. Typically, adapted cells have undergone changes that are similar to changes that take place in cancer cells, and appear to have lost the ability to restrict key factors to factories. Only by studying newly isolated cells will we understand how normal cells maintain their choice of genes, and then be able to understand how this is eroded during the early stages of cancer.Recently we showed that a protein called CIZ1 is required, in normal cells, for a test chromosome to i) acquire key marks and ii) briefly relocate from one position in the nucleus to another position. We think that these two observations are linked and that, by studying the function of CIZ1 we can establish whether targeted delivery of gene to spatially restricted factor normally operates inside the nucleus of normal cells in the body. We aim to use the results to understand how important CIZ1 is to maintain appropriate marks, and so guard against loss of control and emergence of disease. We are specifically concerned with the effect of alterations in CIZ1 (common in early stage cancers of several different types), as experimental removal of CIZ1 promotes the apparent tendency of cultured cells to loosen spatial separation of gene and factor.