Nonlinear control of transcription through enhancer-promoter interactions
Open accessPreprint — published as 10.1038/s41586-022-04570-y · Paper page
Abstract
Chromosome structure in mammals is thought to regulate transcription by modulating the three-dimensional interactions between enhancers and promoters, notably through CTCF-mediated interactions and topologically associating domains (TADs) 1–4 . However, how chromosome interactions are actually translated into transcriptional outputs remains unclear. To address this question we use a novel assay to position an enhancer at a large number 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. Quantitative analysis of hundreds of cell lines reveal that the transcriptional effect of an enhancer depends on its contact probabilities with the promoter through a non-linear relationship. Mathematical modeling and validation against experimental data further provide evidence that nonlinearity arises from transient enhancer-promoter interactions being memorized into longer-lived promoter states in individual cells, thus uncoupling the temporal dynamics of interactions from those of transcription. This uncovers a potential mechanism for how enhancers control transcription across large genomic distances despite rarely meeting their target promoters, and for how TAD boundaries can block distal enhancers. We finally show that enhancer strength additionally determines not only absolute transcription levels, but also the sensitivity of a promoter to CTCF-mediated functional insulation. Our unbiased, systematic and quantitative measurements establish general principles for the context-dependent role of chromosome structure in long-range transcriptional regulation.
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The insulating effect of TAD boundaries may be inversely dependent on enhancer strength.
“Recent mechanistic experiments suggest that the insulating effect of TAD boundaries may be inversely dependent on enhancer strength [405].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [405]
The Main text reports that a weaker enhancer was completely insulated by a CTCF site, whereas the stronger full-length enhancer was not. It also says insulation is context-dependent, but does not establish an inverse relationship specifically for TAD boundaries; it reports complete TAD-boundary insulation even for the strong enhancer. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn Zuin et al.'s systematic study, probabilities of enhancer-promoter contacts showed a strong dependence on linear distance within the TAD and fell sharply near and across TAD boundaries.
“the probabilities of enhancer–promoter contacts showed a strong dependence on linear distance within the TAD and fell sharply near and across the TAD boundaries [405].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [405]
The majority of specific enhancer-promoter loops are highly enriched within, compared with across, TAD boundaries.
“The majority of specific enhancer–promoter loops follow this pattern and are highly enriched within, compared with across, TAD boundaries [277, 401, 405].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [405]
In an ectopic context, the SCR enhancer-Sox2 promoter pair did not show prominent specific interactions, despite clearly detectable transcriptional effects of SCR.
“in the ectopic context this enhancer–promoter pair did not show prominent specific interactions, despite the clearly detectable transcriptional effects of SCR [405].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [405]
An enhancer's contact with a promoter may facilitate the transition of the promoter from a low-activity state to a highly active state, which in turn may generate bursts at a higher frequency.
“they propose that an enhancer’s contact with a promoter may facilitate the transition of the promoter from a low-activity state to a highly active state [405, 406], which in turn may generate bursts at a higher frequency.”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [405]
Promoters may have a memory (hysteresis) of enhancer action.
“This way, promoters may have a “memory” (hysteresis) of enhancer action [405, 406], reviving some early debates on this topic [527].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [405]
The frequency of enhancer-promoter contacts may have non-linear effects on transcriptional output.
“It also follows from these models that the frequency of enhancer–promoter contacts may have non-linear effects on transcriptional output, consistent with experimental observations [405, 503].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [405]
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- Authors
- Zuin, J., Roth, G., Zhan, Y., Cramard, J., Redolfi, J., Piskadlo, E., Mach, P., Kryzhanovska, M., Tihanyi, G., Kohler, H., Meister, P., Smallwood, S., & Giorgetti, L.
- Affiliations
- Friedrich Miescher Institute (CH)
- University of Basel (CH)
- University of Bern (CH)
- Corresponding author
- Giorgetti, Luca
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2021-04-22
- OpenAlex
- W3155272920
- Cited by
- 67
- References
- 56
- Citations by year
- 2025: 7 · 2024: 9 · 2023: 10 · 2022: 25 · 2021: 15 · 2013: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- RePEc: Research Papers in Economics (submittedVersion)
- BORIS (University Library Bern) (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Novartis Foundation
- European Commission (748091, 759366, HORIZON2020)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (192642, 176226)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- enhancer-promoter interactions, long-range transcriptional regulation, chromosome conformation, topologically associating domains, CTCF, TAD boundaries, distal enhancers, chromosome structure
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