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.
This is a theoretical and computational paper using published experimental data.
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- Alistair N Boettiger
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Job Dekker, University of Massachusetts Medical School, United States
- Received: October 25, 2020
- Accepted: June 25, 2021
- Accepted Manuscript published: July 9, 2021 (version 1)
© 2021, Xiao et al.
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