Uncovering hidden enhancers through unbiased in vivo testing
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 devel...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62497-0 |
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| author | 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 von Maydell Yiwen Zhu Javier Lopez-Rios Diane E. Dickel Marco Osterwalder Axel Visel Len A. Pennacchio |
| author_facet | 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 von Maydell Yiwen Zhu Javier Lopez-Rios Diane E. Dickel Marco Osterwalder Axel Visel Len A. Pennacchio |
| author_sort | Brandon J. Mannion |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4e4d15c6a054473b81a0b6534779f7a1 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-4e4d15c6a054473b81a0b6534779f7a12025-08-20T03:43:22ZengNature PortfolioNature Communications2041-17232025-08-0116111110.1038/s41467-025-62497-0Uncovering hidden enhancers through unbiased in vivo testingBrandon J. Mannion0Stella Tran1Ingrid Plajzer-Frick2Catherine S. Novak3Veena Afzal4Jennifer A. Akiyama5Ismael Sospedra-Arrufat6Sarah Barton7Erik Beckman8Tyler H. Garvin9Patrick Godfrey10Janeth Godoy11Riana D. Hunter12Momoe Kato13Michael Kosicki14Anne N. Kronshage15Elizabeth A. Lee16Eman M. Meky17Quan T. Pham18Kianna von Maydell19Yiwen Zhu20Javier Lopez-Rios21Diane E. Dickel22Marco Osterwalder23Axel Visel24Len A. Pennacchio25Environmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadCentro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, and Junta de AndalucíaEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadCentro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, and Junta de AndalucíaEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadDepartment for BioMedical Research (DBMR), University of BernEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadEnvironmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron RoadAbstract 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.https://doi.org/10.1038/s41467-025-62497-0 |
| spellingShingle | 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 von Maydell Yiwen Zhu Javier Lopez-Rios Diane E. Dickel Marco Osterwalder Axel Visel Len A. Pennacchio Uncovering hidden enhancers through unbiased in vivo testing Nature Communications |
| title | Uncovering hidden enhancers through unbiased in vivo testing |
| title_full | Uncovering hidden enhancers through unbiased in vivo testing |
| title_fullStr | Uncovering hidden enhancers through unbiased in vivo testing |
| title_full_unstemmed | Uncovering hidden enhancers through unbiased in vivo testing |
| title_short | Uncovering hidden enhancers through unbiased in vivo testing |
| title_sort | uncovering hidden enhancers through unbiased in vivo testing |
| url | https://doi.org/10.1038/s41467-025-62497-0 |
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