How subtle changes in 3D structure can create large changes in transcription

Abstract
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Abstract

Animal genomes are organized into topologically associated domains (TADs). TADs are thought to contribute to gene regulation by facilitating enhancer-promoter (E-P) contacts within a TAD preventing these contacts across TAD borders. However, the absolute difference in contact frequency across TAD boundaries is usually less than two-fold, even though disruptions of TAD borders can change gene expression by ten-fold. Existing models fail to explain this hypersensitive response. Here, we propose a futile cycle model of enhancer-mediated regulation that can exhibit hypersensitivity through bistability and hysteresis. Consistent with recent experiments, this regulation does not exhibit strong correlation between enhancer-promoter contact and promoter activity, even though regulation occurs through contact. Through mathematical analysis and stochastic simulation, we show that this system can create an illusion of enhancer-promoter biochemical specificity and explain the importance of weak TAD boundaries. It also offers a mechanism to reconcile apparently contradictory results from recent global TAD disruption with local TAD boundary deletion experiments. Together, these analyses advance our understanding of cis-regulatory contacts in controlling gene expression, and suggest new experimental directions.

Data availability

This is a theoretical and computational paper using published experimental data.

The following previously published data sets were used

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(2019) Live-Cell Imaging Reveals Enhancer-Dependent Sox2 Transcription in the Absence of Enhancer Proximity
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https://doi.org/10.7554/eLife.41769
(2014) A three-dimensional map of the human genome at kilobase resolution reveals prinicples of chromatin looping
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Article and author information

Author details

Jordan Yupeng Xiao

Program in Biophysics, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Antonina Hafner

Department of Developmental Biology, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Alistair N Boettiger

Department of Developmental Biology, Stanford University, Stanford, United States

For correspondence
boettiger@stanford.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3554-5196

Funding

National Institutes of Health (U01 DK127419)

Alistair N Boettiger

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.