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

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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

Elizabeth Eck

Biophysics, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Jonathan Liu

Physics, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0204-0105
Maryam Kazemzadeh-Atoufi

Materials Science and Engineering, Northwestern University, Evanston, United States

Competing interests
The authors declare that no competing interests exist.
Sydney Ghoreishi

Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Shelby A Blythe

Department of Molecular Biosciences, Northwestern University, Evanston, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4986-2579
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.

"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.

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.