Shadow enhancers can suppress input transcription factor noise through distinct regulatory logic

Abstract
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Abstract

Shadow enhancers, groups of seemingly redundant enhancers, are found in a wide range of organisms and are critical for robust developmental patterning. However, their mechanism of action is unknown. We hypothesized that shadow enhancers drive consistent expression levels by buffering upstream noise through a separation of transcription factor (TF) inputs at the individual enhancers. By measuring transcriptional dynamics of several Kruppel shadow enhancer configurations in live Drosophila embryos, we showed individual member enhancers act largely independently. We found that TF fluctuations are an appreciable source of noise that the shadow enhancer pair can better buffer than duplicated enhancers. The shadow enhancer pair is uniquely able to maintain low levels of expression noise across a wide range of temperatures. A stochastic model demonstrated the separation of TF inputs is sufficient to explain these findings. Our results suggest the widespread use of shadow enhancers is partially due to their noise suppressing ability.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Code for analyzing the transcriptional traces and for creating the computational models is available on Git Hub: https://github.com/WunderlichLab/KrShadowEnhancerCode.

Article and author information

Author details

Rachel Waymack

Developmental and Cell Biology, University of California, Irvine, Irvine, United States

Competing interests
The authors declare that no competing interests exist.
Alvaro Fletcher

Mathematical, Computational, and System Biology Graduate Program, University of California, Irvine, Irvine, United States

Competing interests
The authors declare that no competing interests exist.
German Enciso

Mathematics, University of California, Irvine, Irvine, United States

Competing interests
The authors declare that no competing interests exist.
Zeba Wunderlich

Developmental and Cell Biology, University of California, Irvine, Irvine, United States

For correspondence
zeba@uci.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4491-5715

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R00-HD073191)

Zeba Wunderlich

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01-HD095246)

Zeba Wunderlich

Hellman Foundation

Zeba Wunderlich

National Institute of Biomedical Imaging and Bioengineering (T32-EB009418)

Alvaro Fletcher

ARCS Foundation

Rachel Waymack

National Science Foundation (DMS1763272)

German Enciso

Simons Foundation (594598)

German Enciso

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.