Cellular Phenotype sequencing (CePh-seq): Decoding the morphological and molecular age-related phenotypes of single cells

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All the cells in our body have the same genetic information, yet different cells which have the same genome display very different properties and do very different things. A large part of these differences comes down to which genes are actually turned on within each cell. It has also been seen that cells which have the same combination of genes being transcribed often look very similar and behave in a similar way, yet understanding the connection between active genes and appearance is very difficult, as there is no automated way to collect cells which all look similar. In this BBSRC project, we will develop a new biotechnology instrument which can take a mixed sample of cells, accurately measure their morphological properties, then select those cells with a particular morphology of interest, barcode them with a unique molecular identifier, and finally measure the activity of all of their genes. The use of the barcode is essential because the process of analysing the genes destroys the cells and only looks at the molecules within the cell. By linking this molecular barcode to the image of the cell before it was destroyed, it will be possible to investigate the relationship between particular genes and how cells look.We will use this new technology to investigate a so far unsolvable problem in ageing which may shed light on how old cells pack their DNA and how this can change the active genes. In particular, we will investigate the changes in the nuclei of cells when they become senescent - a process by which cells stop dividing which is linked to ageing and cancer. It has been observed that the DNA in some senescent cells can rearrange to form a distinctive pattern of bright spots, however the causes and function of such rearrangements are still unknown and difficult to investigate as it is only some of the cells which display the change. By isolating cells based on the arrangement of their DNA, we will be able to investigate what makes these cells different from their companions, which may provide critical insight into understanding the cellular changes of growing old.