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Live imaging of nuclear complexes to decode signalling responses

Supervisor: Sarah Bray

Notch is the receptor in a highly conserved signalling pathway that is of major importance in many developmental and disease contexts. A key feature of Notch signalling is that it directs immediate changes in transcription via the DNA-binding factor CSL, switching it from repression to activation. How Notch can generate both a sensitive and accurate response - in the absence of any amplification step - remains to be elucidated.  To address this question, we developed real-time analysis of CSL dynamics including single molecule tracking in vivo. We found that Notch brings about a change in CSL dynamics via two different mechanisms that together provide a paradigm for how Notch activity is transduced at target loci.  The PhD project will (1) investigate the mechanisms and their relevance for disease (2) explore whether this paradigm is deployed in other signalling pathways.

Relevant references

Bray SJ (2016) Notch Signalling in Context. Nature Reviews in Molecular Cell Biology 17 (11), pp. 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