![]() However, this view has recently been challenged by reports that disruption of TAD boundaries 9, 10 or depletion of CTCF and cohesin 11, 12 do not lead to systematic changes in gene expression, and that some regulatory sequences can act across TAD boundaries 13. TAD boundaries and CTCF loops are thought to favour enhancer–promoter communication within specific genomic regions and disfavour it with respect to surrounding sequences 1, 3, 4, 8. These mainly arise from nested looping interactions between sites that are bound by the DNA-binding protein CTCF that act as barriers for the loop extrusion activity of cohesin 7. Chromosome conformation capture (3C) methods 6 revealed that enhancer–promoter interactions predominantly occur within sub-megabase domains known as topologically associating domains (TADs). ![]() Enhancers are often located hundreds of kilobases away from target promoters and are thought to control gene expression by interacting with the promoters in the three-dimensional space of the nucleus. Transcriptional control in mammals critically depends on enhancers, which control tissue specificity and developmental timing of many genes 5. Our measurements establish general principles for the context-dependent role of chromosome structure in long-range transcriptional regulation. Finally, we show that enhancer strength also determines absolute transcription levels as well as the sensitivity of a promoter to CTCF-mediated transcriptional insulation. This uncovers a potential mechanism of how distal enhancers act from large genomic distances, and of how topologically associating domain boundaries block distal enhancers. Mathematical modelling suggests that nonlinearity might arise from transient enhancer–promoter interactions being translated into slower promoter bursting dynamics in individual cells, therefore uncoupling the temporal dynamics of interactions from those of transcription. ![]() A quantitative analysis of hundreds of cell lines reveals that the transcriptional effect of an enhancer depends on its contact probabilities with the promoter through a nonlinear relationship. Here, to address this question, we use an assay to position an enhancer at large numbers of densely spaced chromosomal locations relative to a fixed promoter, and measure promoter output and interactions within a genomic region with minimal regulatory and structural complexity. However, how chromosome interactions are actually translated into transcriptional outputs remains unclear. Chromosome structure in mammals is thought to regulate transcription by modulating three-dimensional interactions between enhancers and promoters, notably through CTCF-mediated loops and topologically associating domains (TADs) 1, 2, 3, 4. ![]()
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