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Transcriptional interference revisited

Nature Genetics (2026)Cite this article

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Abstract

The transcriptional interference model suggests that RNA polymerases elongating through overlapping transcription units mutually inhibit transcription and disrupt associated cis-regulatory elements. As a longstanding fundamental concept of gene regulation, the idea of reciprocal inhibition between sense and antisense transcription has been supported by a significant body of research. However, despite the model’s biophysical plausibility and historical significance, evidence from large-scale transcriptome studies raises questions about its universal applicability. In particular, the new data indicate that a measurable influence of transcriptional interference is absent from the majority of loci with overlapping transcription. Here we highlight key aspects of overlapping transcription and propose potential solutions to this emerging puzzle. Gaining a better understanding of the molecular mechanisms that render loci sensitive or resistant to interference could lead to groundbreaking insights into the biology of gene regulation.

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Fig. 1: Genomic arrangements of overlapping transcription units that may elicit transcriptional interference.
Fig. 2: Divergent and convergent promoters and enhancers.
Fig. 3: Mechanisms that could help ameliorate the effects of transcriptional interference.

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Acknowledgements

This work was supported by the German Research Foundation (grants HO 5281/7-1 to S.H. and FI 1993/6-1 to M.F.). Funding for open access publication was provided by the Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), Jena, Germany. The FLI is a member of the Leibniz Association and is financially supported by the Federal Government of Germany and the State of Thuringia.

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  1. These authors contributed equally: Martin Fischer, Steve Hoffmann.

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  1. Computational Biology Group, Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), Jena, Germany

    Martin Fischer & Steve Hoffmann

  2. Institute of Biochemistry and Cell Biology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany

    Martin Fischer

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Fischer, M., Hoffmann, S. Transcriptional interference revisited. Nat Genet (2026). https://doi.org/10.1038/s41588-026-02536-8

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