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Optogenetic methods to manipulate Notch activity (Sarah Bray with Maria Gomez-Lamarca)

Supervisor: Sarah Bray (with Maria Gomez-Lamarca)

The Notch pathway is one of a small handful of cell signalling pathways that coordinate development, regulating the types and numbers of cells formed in many developmental contexts. Its’ functions include maintenance of stem/progenitor cells, regulation of cell fates, organizing patterns of growth, and many others. In addition, aberrant Notch activity is implicated in diseases including cancers.

When Notch is activated very rapid changes in gene expression occur. One of our aims is to understand how this occurs: how can a small amount of active receptor change get to the right places in the nucleus to achieve this. One challenge in studying this is that the methods of activating Notch are not easy to manipulate with high precision. Our aim is to develop method(s) that will make it possible to activate the pathway optically. To achieve this we will use different strategies to cage an active form of the Notch receptor. This will entail engineering transgenes where the Notch is fused to light sensitive domains and subsequently investigating the consequences from releasing these using live-imaging to monitor nuclear events. These can be combined with other genetic manipulations to test how the activity is affected when other factors are missing. Ultimately, these tools, combined with methods to track the behaviour of other components in the pathway will be used to generate accurate models of how the active Notch operates inside the cells and how this can be disrupted by disease causing modifications.

Relevant references

Skalska L, Stojnic R, Li J, Fischer B, Cerda-Moya G, Sakai H, Tajbakhsh S, Russell S, Adryan B, Bray SJ (2015) Chromatin signatures at Notch-regulated enhancers reveal large-scale changes in H3K56ac upon activation. EMBO J 34(14): 1889-1904

Krejci, A and Bray, SJ (2007) Notch activation stimulates transient and selective binding of Su(H)/CSL to target enhancers. Genes and Development 21: 1322-7.

Bray, SJ (2006) Notch Signalling: a simple pathway becomes complex. Nature Reviews in Molecular Cell Biology 7: 678-689.

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