Information content differentiates enhancers from silencers in mouse photoreceptors

  1. Ryan Z Friedman
  2. David M Granas
  3. Connie A Myers
  4. Joseph C Corbo
  5. Barak A Cohen
  6. Michael A White  Is a corresponding author
  1. Washington University School of Medicine, United States

Abstract

Enhancers and silencers often depend on the same transcription factors (TFs) and are conflated in genomic assays of TF binding or chromatin state. To identify sequence features that distinguish enhancers and silencers, we assayed massively parallel reporter libraries of genomic sequences targeted by the photoreceptor TF CRX in mouse retinas. Both enhancers and silencers contain more TF motifs than inactive sequences, but relative to silencers, enhancers contain motifs from a more diverse collection of TFs. We developed a measure of information content that describes the number and diversity of motifs in a sequence and found that, while both enhancers and silencers depend on CRX motifs, enhancers have higher information content. The ability of information content to distinguish enhancers and silencers targeted by the same TF illustrates how motif context determines the activity of cis-regulatory sequences.

Data availability

The pJK01 and pJK03 plasmids have been deposited with AddGene (IDs 173489, 173490). Raw sequencing data and barcode counts have been uploaded to the NCBI GEO database under accession GSE165812. All processed activity data, predicted occupancy, and information content values are available in the supplementary material. All code for data processing, analysis, and visualization is available on Github at https://github.com/barakcohenlab/CRX-Information-Content.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ryan Z Friedman

    Edison Family Center for Genome Sciences and Systems Biology, and Department of Genetics, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9013-8676
  2. David M Granas

    Edison Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Connie A Myers

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Joseph C Corbo

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9323-7140
  5. Barak A Cohen

    Edison Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3350-2715
  6. Michael A White

    Edison Family Center for Genome Sciences and Systems Biology, and Department of Genetics, Washington University School of Medicine, St. Louis, United States
    For correspondence
    mawhite@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8511-6026

Funding

National Institutes of Health (F31HG011431)

  • Ryan Z Friedman

National Institutes of Health (R01GM121755)

  • Michael A White

National Institutes of Health (R01EY027784)

  • Barak A Cohen

National Institutes of Health (EY025196)

  • Joseph C Corbo

National Institutes of Health (EY03075)

  • Joseph C Corbo

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to protocol # A-3381-01 approved by the Institutional Animal Care and Use Committee of Washington University in St. Louis. Euthanasia of mice was performed according to the recommendations of the American Veterinary Medical Association Guidelines on Euthanasia. Appropriate measures are taken to minimize pain and discomfort to the animals during experimental procedures.

Reviewing Editor

  1. Naama Barkai, Weizmann Institute of Science, Israel

Publication history

  1. Preprint posted: February 7, 2021 (view preprint)
  2. Received: February 9, 2021
  3. Accepted: September 3, 2021
  4. Accepted Manuscript published: September 6, 2021 (version 1)
  5. Version of Record published: October 5, 2021 (version 2)

Copyright

© 2021, Friedman et al.

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.

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  1. Ryan Z Friedman
  2. David M Granas
  3. Connie A Myers
  4. Joseph C Corbo
  5. Barak A Cohen
  6. Michael A White
(2021)
Information content differentiates enhancers from silencers in mouse photoreceptors
eLife 10:e67403.
https://doi.org/10.7554/eLife.67403

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