Temporal constraints on enhancer usage shape the regulation of limb gene transcription

Article Article scientifique Article Temporal constraints on enhancer usage shape the regulation of limb gene transcription eng 2026-01-12 author Rouco Raquel 0000-0002-0657-0704 927044 author Castro Antonella 843600 Département de médecine génétique et développement (GEDEV) Antonella Rauseo author Darbellay Fabrice 0000-0001-6942-3325 643868 Département de médecine génétique et développement (GEDEV) author Sapin Guillaume Joël 928940 author Bompadre Olimpia 0000-0002-8334-6538 917778 author Delisle Lucille 0000-0002-1964-4960 848639 Département de médecine génétique et développement (GEDEV) author Andrey Guillaume 0000-0002-0911-4907 555493 Département de médecine génétique et développement (GEDEV) 5 10.1038/s41467-025-66055-6 41526337 2041-1723 PMC12795824 https://www.nature.com/articles/s41467-025-66055-6 Enhancer repertoires orchestrate gene expression during embryonic development, shaping organ structure and function. Individual enhancers can act in overlapping or distinct spatial domains, but their temporal specificity and coordinated action over time remain poorly understood. Here, we identify temporally restricted enhancer repertoires at multiple loci involved in mouse limb development. To capture their dynamic roles, we introduce the regulatory trajectory framework comprising initiation, maintenance, and decommissioning of gene expression. Using a transgenic recorder at the Shox2 locus, we demonstrate that early enhancers initiate transcription, while late enhancers maintain it. Additionally, we found that changes in 3D topology associate with enhancer activities and that loss of enhancer-promoter contacts occurs during decommissioning. Finally, we show that Shox2 regulatory decommissioning can be driven by Hoxd13 , a known antagonist of Shox2 expression. Overall, our work uncovers how temporally restricted enhancers generate complex expression patterns and sheds light on the dynamics of enhancer-promoter interactions. Animals Enhancer Elements, Genetic / genetics Extremities / embryology Gene Expression Regulation, Developmental Homeodomain Proteins / genetics Homeodomain Proteins / metabolism Mice Mice, Transgenic Promoter Regions, Genetic / genetics Transcription Factors / genetics Transcription Factors / metabolism Transcription, Genetic Dewey 590 Dewey 576.5 Swiss National Science Foundation Regulatory functions and mechanisms of dynamic chromatin interactions in vivo 176802 CH Swiss National Science Foundation Regulatory functions and mechanisms of dynamic chromatin interactions in vivo 210996 CH Swiss National Science Foundation Unraveling the temporal dynamics of gene regulatory landscapes during limb development 10001978 CH 135 Département de médecine génétique et développement 21D 23 Institut de génétique et de génomique 0DH false 1268 Contrôle épigénétique du développement embryonnaire 999 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE262006 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE84795 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE194114 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE81358 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM8093970 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM8093971 https://github.com/RROUCO/Scripts_for_Rouco_et_al_2025/ https://zenodo.org/records/17143322 https://zenodo.org/records/14865689 Nature communications 17 1 6fe63568-2907-4c5c-beb3-ab99cb5e6372 Article (Published version) Public Article_scientifique_from_crossref.pdf 6006954 application/pdf CC BY-4.0 45839f6f328559535888b20d8bf56c229d0b5a1f9ec490dfffb3f04bba1c01c5 4e3de2c5-305a-4457-be5d-b0c1efe0e921 Supplemental data Public 41467_2025_66055_MOESM1_ESM.pdf 15432976 application/pdf b5eae5c8900b15001fbd7e1586500f9d65a7675480f2a5bf20372315ffd997de a6c16166-0bb6-4bec-bfe0-65e711607fef Supplemental data Public 41467_2025_66055_MOESM2_ESM.pdf 461260 application/pdf dc42c87a88325721b3014515c38cfe183adfb2ea22a820c426e60d6b5741e159 6f1bb54a-30d0-4ae1-ad16-7dc68dbabdb7 Supplemental data Public 41467_2025_66055_MOESM3_ESM.xlsx 73035 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet faa946ecc19a9643fe58aeaa780db144fd440b52d975264b4535b2bb5d2e30f8 35a6af4d-7fa1-469e-882a-a62ccd37e535 Supplemental data Public 41467_2025_66055_MOESM4_ESM.xlsx 8466868 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 194b379a04f9c59fb4797142fcb268f3870b67d7e156699bfb9988908aa26896 68790ea7-66d1-4f3f-8595-36ff292ec193 Supplemental data Public 41467_2025_66055_MOESM5_ESM.xlsx 445460 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 6c5769caaeef62d7f058494a22ffa54e44742cbe2ab818e98a65dd4080517c2f b68dd6bd-2ea1-497b-8819-a528dc807ee5 Supplemental data Public 41467_2025_66055_MOESM6_ESM.xlsx 2199276 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet d964e6d5c691c9fc6632772bf85727ac2919efa73bc6a1a58ade9a012a5d1067 74062bf8-885b-4e77-bf47-4d39672ac71e Supplemental data Public 41467_2025_66055_MOESM7_ESM-1.xlsx 14154 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 6b91071a83de69a0e67363b6b3ff3722acfb3b4935a06ccd4c0b5eb8917f941d bf437217-2074-459a-a95f-c03815649332 Supplemental data Public 41467_2025_66055_MOESM8_ESM.xlsx 20933 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet df9ad20f383d6ce6435c5fe079376d90f6c79d93f215e83e2d959922bb8c9cc4 d1654cbb-1439-4b95-bfed-c0806e01e684 Supplemental data Public 41467_2025_66055_MOESM9_ESM.xlsx 42724023 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 8b460e70c2c4a74a1291354f6beeffd40caa72f733c9f1728c80b33b2d8bf816 46224cf8-f780-43b3-8c74-b2112310a459 Supplemental data Public 41467_2025_66055_MOESM10_ESM-1.xlsx 14423 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 31e3a239d44df56bccdf05c5b0800536f86109cacce5648510ad640aa0d770c4 ced78bc0-f9cf-461d-9a94-3407b7850f78 Supplemental data Public 41467_2025_66055_MOESM11_ESM.pdf 181933 application/pdf a63c26fe925fe9b53339d1667a6e42c753a4a14669d4177afd3ff3dd4376f6ca 9c12f8cb-2032-48aa-b672-19097b959d3c Supplemental data Public 41467_2025_66055_MOESM13_ESM.xlsx 35784 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 51c77620575e574fd8c33b27c19512ff13c0df17ea289a80bb7255cd7ae22543 openAccess Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement Centres et instituts / Institut de génétique et de génomique

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Temporal constraints on enhancer usage shape the regulation of limb gene transcription	Nature communications			2026	44	24

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Delisle, Lucille