For example, many TAD boundaries demarcate regions of co-expressed genes and separate differentially expressed genes, suggesting that they play a role in cis-regulatory specificity ( Long et al., 2016 McCord et al., 2020 Spielmann et al., 2018). Recent microscopy experiments have shown that TADs are a statistical property that emerges from a population of cells dynamically exploring multiple conformational states, rather than a static structure found in all cells ( Bintu et al., 2018).ĭespite broad agreement on the existence of TADs, their role in transcriptional regulation has recently become a subject of controversy as different recent results have been interpreted to support or refute a functional link ( Finn and Misteli, 2019a Ghavi-Helm et al., 2019 Mir et al., 2019). They can be detected by a range of distinct techniques, including methods relying on proximity ligation like 3C/Hi-C ( Jerković et al., 2020 Kempfer and Pombo, 2020 McCord et al., 2020 Rowley and Corces, 2018), ligation-free sequencing methods like GAM ( Beagrie et al., 2017) and SPRITE ( Quinodoz et al., 2018), microscopy methods such as ORCA ( Bintu et al., 2018 Mateo et al., 2019), and even live-cell measurements like DAMC ( Redolfi et al., 2019). When plotted as a heat map of contact frequency as a function of two genomic coordinates, TADs appear as boxes on the diagonal at specific genomic coordinates. The genomes of many organisms have been shown to adopt a domain-like structure commonly referred to as topologically associated domains (TADs) ( Ibrahim and Mundlos, 2020 Jerković et al., 2020 McCord et al., 2020 Rowley and Corces, 2018), defined as contiguous regions of the genome where intra-region 3D proximity is greater than inter-region ( Dixon et al., 2012 Nora et al., 2012). Together, these analyses advance our understanding of cis-regulatory contacts in controlling gene expression and suggest new experimental directions.
It also offers a mechanism to reconcile apparently contradictory results from recent global TAD disruption with local TAD boundary deletion experiments. 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. Consistent with recent experiments, this regulation does not exhibit strong correlation between E-P contact and promoter activity, even though regulation occurs through contact. Here, we propose a futile cycle model of enhancer-mediated regulation that can exhibit hypersensitivity through bistability and hysteresis. Existing models fail to explain this hypersensitive response. 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. 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.
Animal genomes are organized into topologically associated domains (TADs).