Activation of the Notch Signaling Pathway In Vivo Elicits Changes in CSL Nuclear Dynamics

Publication date: Available online 22 February 2018
Source:Developmental Cell
Author(s): Maria J. Gomez-Lamarca, Julia Falo-Sanjuan, Robert Stojnic, Sohaib Abdul Rehman, Leila Muresan, Matthew L. Jones, Zoe Pillidge, Gustavo Cerda-Moya, Zhenyu Yuan, Sarah Baloul, Phillippe Valenti, Kerstin Bystricky, Francois Payre, Kevin O'Holleran, Rhett Kovall, Sarah J. Bray
A key feature of Notch signaling is that it directs immediate changes in transcription via the DNA-binding factor CSL, switching it from repression to activation. How Notch generates 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. In Notch-OFF nuclei, a small proportion of CSL molecules transiently binds DNA, while in Notch-ON conditions CSL recruitment increases dramatically at target loci, where complexes have longer dwell times conferred by the Notch co-activator Mastermind. Surprisingly, recruitment of CSL-related corepressors also increases in Notch-ON conditions, revealing that Notch induces cooperative or "assisted" loading by promoting local increase in chromatin accessibility. Thus, in vivo Notch activity triggers changes in CSL dwell times and chromatin accessibility, which we propose confer sensitivity to small input changes and facilitate timely shut-down.

Teaser

Gomez-Lamarca et al. explore the basis of Notch signaling responsiveness at the transcriptional level through in vivo, real-time analysis of key DNA-binding factor CSL. CSL is highly dynamic with transient DNA residence in the Notch-OFF state. Notch activity increases chromatin accessibility and confers a longer dwell time for response sensitivity.


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