Uncovering hidden enhancers through unbiased in vivo testing

Brandon J. Mannion, Stella Tran, Ingrid Plajzer-Frick, Catherine S. Novak, Veena Afzal, Jennifer A. Akiyama, Ismael Sospedra-Arrufat, Sarah Barton, Erik Beckman, Tyler H. Garvin, Patrick Godfrey, Janeth Godoy, Riana D. Hunter, Momoe Kato, Michael Kosicki, Anne N. Kronshage, Elizabeth A. Lee, Eman M. Meky, Quan T. Pham, Kianna Maydell, Yiwen Zhu, Javier Lopez-Rios, Diane E. Dickel, Marco Osterwalder (), Axel Visel () and Len A. Pennacchio ()
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Brandon J. Mannion: 1 Cyclotron Road
Stella Tran: 1 Cyclotron Road
Ingrid Plajzer-Frick: 1 Cyclotron Road
Catherine S. Novak: 1 Cyclotron Road
Veena Afzal: 1 Cyclotron Road
Jennifer A. Akiyama: 1 Cyclotron Road
Ismael Sospedra-Arrufat: and Junta de Andalucía
Sarah Barton: 1 Cyclotron Road
Erik Beckman: 1 Cyclotron Road
Tyler H. Garvin: 1 Cyclotron Road
Patrick Godfrey: 1 Cyclotron Road
Janeth Godoy: 1 Cyclotron Road
Riana D. Hunter: 1 Cyclotron Road
Momoe Kato: 1 Cyclotron Road
Michael Kosicki: 1 Cyclotron Road
Anne N. Kronshage: 1 Cyclotron Road
Elizabeth A. Lee: 1 Cyclotron Road
Eman M. Meky: 1 Cyclotron Road
Quan T. Pham: 1 Cyclotron Road
Kianna Maydell: 1 Cyclotron Road
Yiwen Zhu: 1 Cyclotron Road
Javier Lopez-Rios: and Junta de Andalucía
Diane E. Dickel: 1 Cyclotron Road
Marco Osterwalder: University of Bern
Axel Visel: 1 Cyclotron Road
Len A. Pennacchio: 1 Cyclotron Road

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Chromatin signatures are widely used to identify tissue-specific in vivo enhancers, but their sensitivity and specificity remains unclear. Here we show that many developmental enhancers remain undetectable using currently available chromatin data. In an initial comparison of over 1200 developmental enhancers with tissue-matched chromatin data, 14% (n = 285) lacked canonical enhancer-associated chromatin signatures. To further assess the prevalence of enhancers missed by chromatin profiling approaches, we used a high-throughput transgenic enhancer assay to screen the regulatory landscapes of two key developmental genes at 5 kb resolution, spanning 1.3 Mb of mouse sequence in total. We observed that 23 of 88 (26%) in vivo enhancers discovered by this approach lacked enhancer-associated chromatin signatures in the respective tissue. Our findings suggest the existence of tens of thousands of enhancers that remain undiscovered by currently available chromatin data, underscoring the continued need for expanding resources for enhancer discovery.

Date: 2025
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DOI: 10.1038/s41467-025-62497-0

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