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Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation

Nature Reviews Molecular Cell Biology volume 25, pages 574–591 (2024)Cite this article

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Abstract

The primary regulators of metazoan gene expression are enhancers, originally functionally defined as DNA sequences that can activate transcription at promoters in an orientation-independent and distance-independent manner. Despite being crucial for gene regulation in animals, what mechanisms underlie enhancer selectivity for promoters, and more fundamentally, how enhancers interact with promoters and activate transcription, remain poorly understood. In this Review, we first discuss current models of enhancer–promoter interactions in space and time and how enhancers affect transcription activation. Next, we discuss different mechanisms that mediate enhancer selectivity, including repression, biochemical compatibility and regulation of 3D genome structure. Through 3D polymer simulations, we illustrate how the ability of 3D genome folding mechanisms to mediate enhancer selectivity strongly varies for different enhancer–promoter interaction mechanisms. Finally, we discuss how recent technical advances may provide new insights into mechanisms of enhancer–promoter interactions and how technical biases in methods such as Hi-C and Micro-C and imaging techniques may affect their interpretation.

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Fig. 1: Models of enhancer–promoter interactions.
Fig. 2: Models of transcription activation by enhancers.
Fig. 3: Models of enhancer selectivity.
Fig. 4: Interpreting the results of conformation capture assays.
Fig. 5: Enhancer selectivity mediated by 3D genome organization as a function of interaction radius.
Fig. 6: Examples of enhancer–promoter pairs with different CTCF binding patterns.
Fig. 7: Interpreting imaging studies of enhancer–promoter interactions.

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Acknowledgements

The authors thank L. Mirny, S. Grosse-Holz, H. Pinholt, M. Mir, C. Hong, M. Gabriele, M. Mazzocca and the rest of the Hansen laboratory for insightful discussions and comments on the manuscript. J.H.Y. was supported by the MathWorks Engineering Fellowship and a graduate fellowship from the Ludwig Center at MIT’s Koch Institute for Integrative Cancer Research. This work was supported by the National Institutes of Health (grant numbers R00GM130896, DP2GM140938, R33CA257878, UM1HG011536), the National Science Foundation (grant 2036037) and a Pew-Stewart Cancer Research Scholar grant.

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Authors and Affiliations

  1. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Jin H. Yang & Anders S. Hansen

  2. Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Jin H. Yang & Anders S. Hansen

  3. Koch Institute for Integrative Cancer Research, Cambridge, MA, USA

    Jin H. Yang & Anders S. Hansen

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J.H.Y. researched data for the article. Both authors contributed substantially to discussion of the content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Anders S. Hansen.

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Nature Reviews Molecular Cell Biology thanks Thomas Milne, Marieke Oudelaar with Abrar Aljahani, and Ranjith Padinhateeri for their contribution to the peer review of this work.

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Supplementary information

Glossary

Architectural proteins

Proteins that regulate 3D chromatin structure by forming chromatin loops and domains, which can regulate interactions between enhancers and promoters.

Biochemical compatibility

The intrinsic ability for an enhancer to activate transcription at some promoters but not others, which may be determined by the binding profile of transcription factors and co-activators.

Chromatic aberrations

Owing to the refractive index varying with the wavelength of light, a perfectly colocalizing E–P pair (true distance of 0 nm) may be measured as being far apart. Very accurate correction of chromatic aberrations is required for precise measurements of E–P distances.

Clustering

A cluster corresponds to higher-than-expected local density of molecules. The term cluster is agnostic to the mechanism of cluster formation and clusters are often defined using spatial statistics.

Condensates

Refers to formation of membraneless compartments of high local concentration of factors through liquid–liquid phase separation.

Co-repressors

Enzymatic complexes recruited to DNA directly or indirectly by transcription factors to establish and maintain repression of transcription.

Enhanceosome

A protein complex that assembles on an enhancer to regulate the transcription of the cognate promoter.

Enhancer RNAs

Non-coding RNAs transcribed from enhancers, which may have gene regulatory functions.

E–P interaction radius

The maximum 3D distance between an enhancer and a promoter that enables them to functionally interact.

Facilitator

Refers to DNA–protein complexes such as DNA-bound CTCF, which can increase the interaction probability between promoters and regulatory elements such as enhancers and silencers.

First-passage time

The time taken for a stochastic process to reach a specific state for the first time, for example, the time taken for an enhancer to find and interact with a promoter.

Hub

Discrete nuclear domains of high transcription protein concentration, which serve as a focal point of activity; ‘hub formation’ is often used to indicate a formation mechanism that is distinct from phase separation.

Insulators

DNA elements bound by specific protein complexes, which may reduce gene expression when placed between an enhancer and a promoter, presumably by reducing the probability of their interaction.

Intrinsically disordered regions

Protein segments lacking well-defined 3D structure in physiological conditions, which form dynamic ensembles of conformations and may engage in multivalent interactions.

Mean squared displacement

The average of the squared displacement of a particle or locus with respect to a reference position, usually calculated over a range of time intervals.

Rouse dynamics

The movement and behaviour of polymers in a bead–spring model, in which monomers are connected by Hookean springs and a monomer only interacts with its nearest neighbours.

Silencers

Regulatory DNA elements that reduce transcription at cognate promoters, including from far away in the genome.

Super-enhancers

Genomic regions consisting of multiple enhancers that can drive high level of transcription at cognate promoters; originally defined based on Mediator enrichment.

Transcription memory

The phenomenon in which the influence of a stimulus persists beyond the initial exposure to the stimulus, including promoter memory of past E–P interactions.

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Yang, J.H., Hansen, A.S. Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation. Nat Rev Mol Cell Biol 25, 574–591 (2024). https://doi.org/10.1038/s41580-024-00710-6

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