1. Physics of Living Systems
Download icon

Quantitative dissection of transcription in development yields evidence for transcription factor-driven chromatin accessibility

  1. Elizabeth Eck
  2. Jonathan Liu
  3. Maryam Kazemzadeh-Atoufi
  4. Sydney Ghoreishi
  5. Shelby A Blythe
  6. Hernan G Garcia  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Northwestern University, United States
Research Article
  • Cited 3
  • Views 2,465
  • Annotations
Cite this article as: eLife 2020;9:e56429 doi: 10.7554/eLife.56429

Abstract

Thermodynamic models of gene regulation can predict transcriptional regulation in bacteria, but in eukaryotes chromatin accessibility and energy expenditure may call for a different framework. Here we systematically tested the predictive power of models of DNA accessibility based on the Monod-Wyman-Changeux (MWC) model of allostery, which posits that chromatin fluctuates between accessible and inaccessible states. We dissected the regulatory dynamics of hunchback by the activator Bicoid and the pioneer-like transcription factor Zelda in living Drosophila embryos and showed that no thermodynamic or non-equilibrium MWC model can recapitulate hunchback transcription. Therefore, we explored a model where DNA accessibility is not the result of thermal fluctuations but is catalyzed by Bicoid and Zelda, possibly through histone acetylation, and found that this model can predict hunchback dynamics. Thus, our theory-experiment dialogue uncovered potential molecular mechanisms of transcriptional regulatory dynamics, a key step toward reaching a predictive understanding of developmental decision-making.

Data availability

Processed microscopy data have been deposited in Dryad (https://datadryad.org/stash/share/zakb7AqU2233pgWIs1mMAKyDiTQi4BXtnP0-Uu93xI0).

Article and author information

Author details

  1. Elizabeth Eck

    Biophysics, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jonathan Liu

    Physics, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0204-0105
  3. Maryam Kazemzadeh-Atoufi

    Materials Science and Engineering, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sydney Ghoreishi

    Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Shelby A Blythe

    Department of Molecular Biosciences, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4986-2579
  6. Hernan G Garcia

    Molecular and Cell Biology, Physics, University of California, Berkeley, Berkeley, United States
    For correspondence
    hggarcia@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5212-3649

Funding

National Science Foundation (Graduate Student Fellowship)

  • Elizabeth Eck

National Institutes of Health (DP2 OD024541-01)

  • Hernan G Garcia

National Science Foundation (1652236)

  • Hernan G Garcia

University of California, Berkeley (Chancellor's Fellowship)

  • Elizabeth Eck

Department of Defense (Graduate Student Fellowship)

  • Jonathan Liu

Burroughs Wellcome Fund (Career Award)

  • Hernan G Garcia

Sloan Research Foundation

  • Hernan G Garcia

Human Frontiers Science Program

  • Hernan G Garcia

Searle Scholars Program

  • Hernan G Garcia

Shurl and Kay Curci Foundation

  • Hernan G Garcia

Hellman Foundation

  • Hernan G Garcia

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

Reviewing Editor

  1. Pierre Sens, Institut Curie, PSL Research University, CNRS, France

Publication history

  1. Received: February 27, 2020
  2. Accepted: October 16, 2020
  3. Accepted Manuscript published: October 19, 2020 (version 1)
  4. Version of Record published: December 15, 2020 (version 2)

Copyright

© 2020, Eck 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.

Metrics

  • 2,465
    Page views
  • 431
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Evolutionary Biology
    2. Physics of Living Systems
    Damián G Hernández et al.
    Research Article Updated

    Although different animal species often exhibit extensive variation in many behaviors, typically scientists examine one or a small number of behaviors in any single study. Here, we propose a new framework to simultaneously study the evolution of many behaviors. We measured the behavioral repertoire of individuals from six species of fruit flies using unsupervised techniques and identified all stereotyped movements exhibited by each species. We then fit a Generalized Linear Mixed Model to estimate the intra- and inter-species behavioral covariances, and, by using the known phylogenetic relationships among species, we estimated the (unobserved) behaviors exhibited by ancestral species. We found that much of intra-specific behavioral variation has a similar covariance structure to previously described long-time scale variation in an individual’s behavior, suggesting that much of the measured variation between individuals of a single species in our assay reflects differences in the status of neural networks, rather than genetic or developmental differences between individuals. We then propose a method to identify groups of behaviors that appear to have evolved in a correlated manner, illustrating how sets of behaviors, rather than individual behaviors, likely evolved. Our approach provides a new framework for identifying co-evolving behaviors and may provide new opportunities to study the mechanistic basis of behavioral evolution.

    1. Neuroscience
    2. Physics of Living Systems
    Kelsey M Hallinen et al.
    Research Article Updated

    We investigated the neural representation of locomotion in the nematode C. elegans by recording population calcium activity during movement. We report that population activity more accurately decodes locomotion than any single neuron. Relevant signals are distributed across neurons with diverse tunings to locomotion. Two largely distinct subpopulations are informative for decoding velocity and curvature, and different neurons’ activities contribute features relevant for different aspects of a behavior or different instances of a behavioral motif. To validate our measurements, we labeled neurons AVAL and AVAR and found that their activity exhibited expected transients during backward locomotion. Finally, we compared population activity during movement and immobilization. Immobilization alters the correlation structure of neural activity and its dynamics. Some neurons positively correlated with AVA during movement become negatively correlated during immobilization and vice versa. This work provides needed experimental measurements that inform and constrain ongoing efforts to understand population dynamics underlying locomotion in C. elegans.