Gene regulation gravitates towards either addition or multiplication when combining the effects of two signals

  1. Eric M Sanford
  2. Benjamin L Emert
  3. Allison Coté
  4. Arjun Raj  Is a corresponding author
  1. University of Pennsylvania, United States

Abstract

Two different cell signals often affect transcription of the same gene. In such cases, it is natural to ask how the combined transcriptional response compares to the individual responses. The most commonly used mechanistic models predict additive or multiplicative combined responses, but a systematic genome-wide evaluation of these predictions is not available. Here, we analyzed the transcriptional response of human MCF-7 cells to retinoic acid and TGF-β, applied individually and in combination. The combined transcriptional responses of induced genes exhibited a range of behaviors, but clearly favored both additive and multiplicative outcomes. We performed paired chromatin accessibility measurements and found that increases in accessibility were largely additive. There was some association between super-additivity of accessibility and multiplicative or super-multiplicative combined transcriptional responses, while sub-additivity of accessibility associated with additive transcriptional responses. Our findings suggest that mechanistic models of combined transcriptional regulation must be able to reproduce a range of behaviors.

Data availability

We have uploading our data to NIH GEO. We are committed to sharing this manuscript's data openly and will happily upload it to any additional databases if requested.All of our raw and processed data (RNA-seq and ATAC-seq data sets) are also available on Dropbox and Github:Data:https://www.dropbox.com/sh/fhx7huyhhtf8fux/AACKW5Bd7k34uy6Rrk3k0WZ4a?dl=0&lst=Analysis Code:https://github.com/emsanford/combined_responses_paperhttps://github.com/arjunrajlaboratory/atac-seq_pipeline_paired-endhttps://github.com/arjunrajlaboratory/RajLabSeqTools

The following data sets were generated

Article and author information

Author details

  1. Eric M Sanford

    Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9232-9334
  2. Benjamin L Emert

    Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  3. Allison Coté

    Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  4. Arjun Raj

    Department of Bioengineering, University of Pennsylvania, Philadelphia, United States
    For correspondence
    arjunraj@seas.upenn.edu
    Competing interests
    Arjun Raj, Receives consulting income and royalties related to Stellaris{trade mark, serif} RNA FISH probes..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2915-6960

Funding

National Institutes of Health (R01 CA238237)

  • Arjun Raj

National Institutes of Health (T32 GM007170)

  • Benjamin L Emert

National Institutes of Health (T32 HG000046)

  • Benjamin L Emert

National Institutes of Health (T32 GM- 07229)

  • Allison Coté

Tara Miller Foundation

  • Arjun Raj

National Institutes of Health (SPORE P50 CA174523)

  • Arjun Raj

National Institutes of Health (F30 HG010986)

  • Eric M Sanford

National Institutes of Health (Transformative Research Award R01 GM137425)

  • Arjun Raj

National Institutes of Health (R01 CA232256)

  • Arjun Raj

National Science Foundation (CAREER 1350601)

  • Arjun Raj

National Institutes of Health (U01 CA227550)

  • Arjun Raj

National Institutes of Health (U01 HL129998)

  • Arjun Raj

National Institutes of Health (RM1 HG007743)

  • Arjun Raj

National Institutes of Health (P30 CA016520)

  • Arjun Raj

National Institutes of Health (F30 CA236129)

  • Benjamin L Emert

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

Reviewing Editor

  1. Jie Xiao, Johns Hopkins University, United States

Publication history

  1. Received: May 28, 2020
  2. Accepted: December 4, 2020
  3. Accepted Manuscript published: December 7, 2020 (version 1)
  4. Version of Record published: December 29, 2020 (version 2)

Copyright

© 2020, Sanford 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. Eric M Sanford
  2. Benjamin L Emert
  3. Allison Coté
  4. Arjun Raj
(2020)
Gene regulation gravitates towards either addition or multiplication when combining the effects of two signals
eLife 9:e59388.
https://doi.org/10.7554/eLife.59388

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