Journal Article

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

Boettiger, Alistair N, Hafner, Antonina, Xiao, Jordan Yupeng

2021

Overview

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 and preventing these contacts across TAD borders. However, the absolute difference in contact frequency across TAD boundaries is usually less than 2-fold, even though disruptions of TAD borders can change gene expression by 10-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 E-P 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 E-P 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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: 3D genome / Analysis / Boundaries / Chromosomes and Gene Expression / Computational and Systems Biology / Embryos / Experiments / Gene expression / Gene regulation / Genes / Genetic research / Genetic transcription / Genomes / Genomics / Hypersensitive response / Hypersensitivity / Insects / Mathematical models / Microscopy / Numerical analysis / Population / stochastic modeling / TAD / Transcription