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  • Perspective
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A transcription coupling model for how enhancers communicate with their target genes

Nature Structural & Molecular Biology volume 32, pages 598–606 (2025)Cite this article

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Abstract

How enhancers communicate with their target genes to influence transcription is an unresolved question of fundamental importance. Current models of the mechanism of enhancer–target gene or enhancer–promoter (E–P) communication are transcription-factor-centric and underappreciate major findings, including that enhancers are themselves transcribed by RNA polymerase II, which correlates with enhancer activity. In this Perspective, we posit that enhancer transcription and its products, enhancer RNAs, are elementary components of enhancer–gene communication. Specifically, we discuss the possibility that transcription at enhancers and at their cognate genes are linked and that this coupling is at the basis of how enhancers communicate with their targets. This model of transcriptional coupling between enhancers and their target genes is supported by growing experimental evidence and represents a synthesis of recent key discoveries.

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Fig. 1: RNA polymerase II-mediated transcription at genes and their cognate enhancers.
Fig. 2: Transcription coupling model of enhancer–target gene communication.
Fig. 3: Mechanisms of eRNA-mediated transcription coupling between enhancer and target gene regions.

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Acknowledgements

We apologize to our colleagues whose work was not cited owing to space constraints. This Perspective was strongly improved by critical feedback from D. M. Ibrahim, L. Behrens, A. Bressin and G. J. Villafano. The original figures were created with Biorender.com. This work was supported by the Max Planck Society.

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Authors and Affiliations

  1. Otto-Warburg-Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany

    Elisabeth Altendorfer & Andreas Mayer

  2. Development and Disease group, Max Planck Institute for Molecular Genetics, Berlin, Germany

    Stefan Mundlos

  3. Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany

    Stefan Mundlos

Authors
  1. Elisabeth Altendorfer
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  2. Stefan Mundlos
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  3. Andreas Mayer
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Contributions

E.A. prepared the original figures and helped write the manuscript. S.M. provided conceptual help. A.M. conceptualized the transcription coupling model and had overall responsibility for this work. A.M. wrote the manuscript with input from all authors.

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Correspondence to Andreas Mayer.

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Nature Structural & Molecular Biology thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Eytan Zlotorynski & Dimitris Typas, in collaboration with the Nature Structural & Molecular Biology team.

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Altendorfer, E., Mundlos, S. & Mayer, A. A transcription coupling model for how enhancers communicate with their target genes. Nat Struct Mol Biol 32, 598–606 (2025). https://doi.org/10.1038/s41594-025-01523-7

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