4.7 Article

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

期刊

DEVELOPMENTAL CELL
卷 44, 期 5, 页码 611-+

出版社

CELL PRESS
DOI: 10.1016/j.devcel.2018.01.020

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资金

  1. Medical Research Council [MR/L007177/1, MR/K015850/1]
  2. Wellcome Trust [099130/Z/12/Z, 099744/Z/12/Z]
  3. NIH [CA178974]
  4. ANR
  5. CNRS
  6. EPSRC [EP/L015455/1]
  7. BBSRC [BB/J014540/1]
  8. NATIONAL CANCER INSTITUTE [R01CA178974] Funding Source: NIH RePORTER
  9. EPSRC [EP/R025398/1] Funding Source: UKRI
  10. MRC [MR/L007177/1, MR/K015850/1] Funding Source: UKRI
  11. Biotechnology and Biological Sciences Research Council [1502069] Funding Source: researchfish
  12. Engineering and Physical Sciences Research Council [EP/R025398/1] Funding Source: researchfish

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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.

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