Mannion, Brandon J. , Tran, Stella , Plajzer-Frick, Ingrid , Novak, Catherine S. , Afzal, Veena , Akiyama, Jennifer A. , Sospedra-Arrufat, 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 MORENO, JAVIER, Dickel, Diane E. , Osterwalder, Marco , Visel, Axel , Pennacchio, Len A.
No
Nat. Commun.
Article
Científica
08/08/2025
001545763500001
2-s2.0-105012730962
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.
transcription factor; bioassay; biological development; cancer; developmental stage; adult; anatomical concepts; Article; binding site; chromatin; chromatin immunoprecipitation sequencing; controlled study; developmental gene; embryo; enhancer region; female; forebrain; functional enrichment analysis; gene; genetic conservation; human; in vivo study; male; mesencephalon; mouse; newborn; nonhuman; phenotype; prevalence; rhombencephalon; animal; antibody specificity; gene expression regulation; genetics; metabolism; transgenic mouse; Animals; Chromatin; Enhancer Elements, Genetic; Gene Expression Regulation, Developmental; Mice; Mice, Transgenic; Organ Specificity