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 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.
Highlights
The upstream domain contained the gene Ubx and its enhancers, and the downstream region contained the gene abd-A and its enhancers (Fig. 1A). We wondered whether these apparent contradictions can be reasonably reconciled with known biochemical mechanisms. To answer these questions we examined simple biophysical models of proximity-dependent E-P communication grounded in known physical laws
Paradoxes and apparent contradictions arising from recent experimental results are reconciled by a minimal model of promoter activity
We set out to understand one paradox: what molecular mechanisms, if any, could enable subtle changes in chromatin structure to lead to large changes in transcription? We developed a futile cycle model and described two possible biochemical realizations/versions which both exhibit hypersensitivity and hysteresis: transcription factors (TFs) condensates and post-transcriptional modification (PTM) accumulation
Summary
The genomes of many organisms have been shown to adopt a domain-like structure commonly referred to as topologically associated domains or 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). 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 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). Many TAD boundaries demarcate regions of co-expressed genes and separate differentially expressed genes, suggesting they play a role in cis-regulatory specificity (Long et al, 2016; McCord et al, 2020; Spielmann et al, 2018). Recent microscopy experiments uncovered little correlation between enhancer-promoter (E-P)
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