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Programming the Notch response: optogenetic strategies to manipulate pathway activity

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. A major focus of the work in the lab is on understanding how the Notch pathway operates and what enables its different functional outcomes.

Recently we have developed methods that allow us to follow specific target genes in living cells making it possible to investigate nuclear events including how the 3D genome organization, the transcription factor dynamics and the chromatin influence the selection of gene targets. A remaining challenge is how to activate Notch with high precision. To achieve this we will adopt optogenetic methods to uncage an active form of the Notch receptor, by fusing it to light sensitive domains. Ultimately, these optogenetic 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 a cell to target the correct genes and how this can be disrupted by disease causing modifications.

Relevant references

Bray, SJ (2016) Notch signalling in Context. Nature Reviews in Molecular and Cellular Biology 7(11):722-735

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.

 

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