Enhancer Priming Enables Fast and Sustained Transcriptional Responses to Notch Signaling

Julia Falo-Sanjuan,Nicholas C Lammers,Hernan G Garcia,Sarah J Bray

doi:10.1016/j.devcel.2019.07.002

Julia Falo-Sanjuan, Nicholas C Lammers + Show 2 more

Open Access

https://doi.org/10.1016/j.devcel.2019.07.002

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Abstract

SummaryInformation from developmental signaling pathways must be accurately decoded to generate transcriptional outcomes. In the case of Notch, the intracellular domain (NICD) transduces the signal directly to the nucleus. How enhancers decipher NICD in the real time of developmental decisions is not known. Using the MS2-MCP system to visualize nascent transcripts in single cells in Drosophila embryos, we reveal how two target enhancers read Notch activity to produce synchronized and sustained profiles of transcription. By manipulating the levels of NICD and altering specific motifs within the enhancers, we uncover two key principles. First, increased NICD levels alter transcription by increasing duration rather than frequency of transcriptional bursts. Second, priming of enhancers by tissue-specific transcription factors is required for NICD to confer synchronized and sustained activity; in their absence, transcription is stochastic and bursty. The dynamic response of an individual enhancer to NICD thus differs depending on the cellular context.

Highlights

Genes respond to external and internal cues through the actions of transcription factors and effectors of signaling pathways
Steroids increase the bursting frequency of target enhancers (Larson et al, 2013; Fritzsch et al, 2018). It remains to be discovered whether all transcription factors alter transcription dynamics in this way and whether it is these or other properties that are modulated by developmental signals to confer appropriate outputs in the in vivo setting of a developing organism
Synchronized and Sustained Enhancer Activation in Response to Notch To investigate how Notch signals are read out by an enhancer in real time, we focused on well-characterized MSE enhancers from the Enhancer of split-Complex (E(spl)-C) and from singleminded (Morel and Schweisguth, 2000; Cowden and Levine, 2002; Zinzen et al, 2006a)

Summary

Introduction

Genes respond to external and internal cues through the actions of transcription factors and effectors of signaling pathways. Enhancers could respond in a digital manner, working as simple on-off switches, or as analog devices, operating as a rheostat so that signal levels can modulate the output (Blackwood and Kadonaga, 1998; Garcia et al, 2013; Lammers et al, 2018) In either case, they must have the capability to detect and transduce key parameters to the transcription machinery, such as signal duration and thresholds. Steroids increase the bursting frequency of target enhancers (Larson et al, 2013; Fritzsch et al, 2018) It remains to be discovered whether all transcription factors alter transcription dynamics in this way and whether it is these or other properties that are modulated by developmental signals to confer appropriate outputs in the in vivo setting of a developing organism

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