Nonlinear control of transcription through enhancer–promoter interactions

Jessica Zuin, Gregory Roth, Yinxiu Zhan, Julie Cramard, Josef Redolfi, Ewa Piskadlo, Pia Mach, Mariya Kryzhanovska, Gergely Tihanyi, Hubertus Kohler, Mathias Eder, Christ Leemans, Bas Steensel, Peter Meister, Sebastien Smallwood and Luca Giorgetti ()
Additional contact information
Jessica Zuin: Friedrich Miescher Institute for Biomedical Research
Gregory Roth: Friedrich Miescher Institute for Biomedical Research
Yinxiu Zhan: Friedrich Miescher Institute for Biomedical Research
Julie Cramard: Friedrich Miescher Institute for Biomedical Research
Josef Redolfi: Friedrich Miescher Institute for Biomedical Research
Ewa Piskadlo: Friedrich Miescher Institute for Biomedical Research
Pia Mach: Friedrich Miescher Institute for Biomedical Research
Mariya Kryzhanovska: Friedrich Miescher Institute for Biomedical Research
Gergely Tihanyi: Friedrich Miescher Institute for Biomedical Research
Hubertus Kohler: Friedrich Miescher Institute for Biomedical Research
Mathias Eder: Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute
Christ Leemans: Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute
Bas Steensel: Division of Gene Regulation and Oncode Institute, Netherlands Cancer Institute
Peter Meister: University of Bern
Sebastien Smallwood: Friedrich Miescher Institute for Biomedical Research
Luca Giorgetti: Friedrich Miescher Institute for Biomedical Research

Nature, 2022, vol. 604, issue 7906, 571-577

Abstract: Abstract 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)1–4. However, how chromosome interactions are actually translated into transcriptional outputs remains unclear. 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. 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. 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. This uncovers a potential mechanism of how distal enhancers act from large genomic distances, and of how topologically associating domain boundaries block distal enhancers. Finally, we show that enhancer strength also determines absolute transcription levels as well as the sensitivity of a promoter to CTCF-mediated transcriptional insulation. Our measurements establish general principles for the context-dependent role of chromosome structure in long-range transcriptional regulation.

Date: 2022
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DOI: 10.1038/s41586-022-04570-y

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