Uncovering hidden enhancers through unbiased in vivo testing

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...

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Autores: Mannion, Brandon J., Tran, Stella, Plajzer-Frick, Ingrid, Novak, Catherine S., Afzal, Veena, Akiyama, Jennifer A, Sospedra, Ismael, Barton, Sarah, Beckman, Erik, Garvin, Tyler H., Godfrey, Patrick, Godoy, Janeth, Hunter, Riana D., Kato, Momoe, Kosicki, Michael, Kronshage, Anne N., Lee, Elizabeth A., Meky, Eman M., Pham, Quan T., von Maydell, Kianna, Zhu, Yiwen, López-Ríos, Javier, Dickel, Diane E., Osterwalder, Marco, Visel, Axel, Pennacchio, Len A
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/422564
Acceso en línea:http://hdl.handle.net/10261/422564
https://api.elsevier.com/content/abstract/scopus_id/105012730962
Access Level:acceso abierto
Palabra clave:Epigenomics
Gene regulation
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spelling Uncovering hidden enhancers through unbiased in vivo testingMannion, Brandon J.Tran, StellaPlajzer-Frick, IngridNovak, Catherine S.Afzal, VeenaAkiyama, Jennifer ASospedra, IsmaelBarton, SarahBeckman, ErikGarvin, Tyler H.Godfrey, PatrickGodoy, JanethHunter, Riana D.Kato, MomoeKosicki, MichaelKronshage, Anne N.Lee, Elizabeth A.Meky, Eman M.Pham, Quan T.von Maydell, KiannaZhu, YiwenLópez-Ríos, JavierDickel, Diane E.Osterwalder, MarcoVisel, AxelPennacchio, Len AEpigenomicsGene regulationChromatin 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.This work was supported by U.S. National Institutes of Health (NIH) grants to L.A.P. and A.V. (UM1HG009421 and R01HG003988). M.O. was supported by the Swiss National Science Foundation (SNSF) grant PCEFP3_186993. J.L.R. was supported by grant PID2023-148267NB-I00 (MICIU/AEI/10.13039/501100011033). Research was conducted at the E.O. Lawrence Berkeley National Laboratory and performed under U.S. Department of Energy Contract DE-AC02-05CH11231, University of California (UC).Peer reviewedSpringer NatureNational Institutes of Health (US)Swiss National Science FoundationMinisterio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)Department of Energy (US)University of CaliforniaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/422564https://api.elsevier.com/content/abstract/scopus_id/105012730962reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2023-148267NB-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s41467-025-62497-0https://doi.org/10.1038/s41467-025-62497-0Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4225642026-05-22T06:33:51Z
dc.title.none.fl_str_mv Uncovering hidden enhancers through unbiased in vivo testing
title Uncovering hidden enhancers through unbiased in vivo testing
spellingShingle Uncovering hidden enhancers through unbiased in vivo testing
Mannion, Brandon J.
Epigenomics
Gene regulation
title_short 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_sort Uncovering hidden enhancers through unbiased in vivo testing
dc.creator.none.fl_str_mv Mannion, Brandon J.
Tran, Stella
Plajzer-Frick, Ingrid
Novak, Catherine S.
Afzal, Veena
Akiyama, Jennifer A
Sospedra, Ismael
Barton, Sarah
Beckman, Erik
Garvin, Tyler H.
Godfrey, Patrick
Godoy, Janeth
Hunter, Riana D.
Kato, Momoe
Kosicki, Michael
Kronshage, Anne N.
Lee, Elizabeth A.
Meky, Eman M.
Pham, Quan T.
von Maydell, Kianna
Zhu, Yiwen
López-Ríos, Javier
Dickel, Diane E.
Osterwalder, Marco
Visel, Axel
Pennacchio, Len A
author Mannion, Brandon J.
author_facet Mannion, Brandon J.
Tran, Stella
Plajzer-Frick, Ingrid
Novak, Catherine S.
Afzal, Veena
Akiyama, Jennifer A
Sospedra, Ismael
Barton, Sarah
Beckman, Erik
Garvin, Tyler H.
Godfrey, Patrick
Godoy, Janeth
Hunter, Riana D.
Kato, Momoe
Kosicki, Michael
Kronshage, Anne N.
Lee, Elizabeth A.
Meky, Eman M.
Pham, Quan T.
von Maydell, Kianna
Zhu, Yiwen
López-Ríos, Javier
Dickel, Diane E.
Osterwalder, Marco
Visel, Axel
Pennacchio, Len A
author_role author
author2 Tran, Stella
Plajzer-Frick, Ingrid
Novak, Catherine S.
Afzal, Veena
Akiyama, Jennifer A
Sospedra, Ismael
Barton, Sarah
Beckman, Erik
Garvin, Tyler H.
Godfrey, Patrick
Godoy, Janeth
Hunter, Riana D.
Kato, Momoe
Kosicki, Michael
Kronshage, Anne N.
Lee, Elizabeth A.
Meky, Eman M.
Pham, Quan T.
von Maydell, Kianna
Zhu, Yiwen
López-Ríos, Javier
Dickel, Diane E.
Osterwalder, Marco
Visel, Axel
Pennacchio, Len A
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv National Institutes of Health (US)
Swiss National Science Foundation
Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
Department of Energy (US)
University of California
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Epigenomics
Gene regulation
topic Epigenomics
Gene regulation
description 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.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/422564
https://api.elsevier.com/content/abstract/scopus_id/105012730962
url http://hdl.handle.net/10261/422564
https://api.elsevier.com/content/abstract/scopus_id/105012730962
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2023-148267NB-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s41467-025-62497-0
https://doi.org/10.1038/s41467-025-62497-0
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
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