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Particularly for enhancers, these models excel at deciphering sequence grammar that underlies their activity. To enable end-to-end enhancer modeling and design, we developed a software package called CREsted (\n                    <jats:italic>cis<\/jats:italic>\n                    -regulatory element sequence training, explanation and design). It combines preprocessing and analysis of single-cell assay for transposase-accessible chromatin using sequencing data, modeling chromatin accessibility from sequence, sequence design and downstream analysis to decipher enhancer grammar. We demonstrate CREsted\u2019s functionality on a mouse cortex and a human peripheral blood mononuclear cell dataset. Additionally, we use CREsted to compare mesenchymal-like cancer cell states between tumor types, and we investigate different fine-tuning strategies of genomic foundation models within CREsted. Finally, we train a model on a zebrafish development atlas and use this to design and in vivo validate cell-type-specific enhancers. For varying datasets, we demonstrate that CREsted facilitates efficient training and analyses, enabling scrutinization of the enhancer logic and design of synthetic enhancers across tissues and species.\n                  <\/jats:p>","DOI":"10.1038\/s41592-026-03057-2","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T09:02:31Z","timestamp":1775120551000},"page":"946-959","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["CREsted: modeling genomic and synthetic cell-type-specific enhancers across tissues and species"],"prefix":"10.1038","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0104-4844","authenticated-orcid":false,"given":"Niklas","family":"Kempynck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7907-1247","authenticated-orcid":false,"given":"Seppe","family":"De Winter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8145-9726","authenticated-orcid":false,"given":"Casper H.","family":"Blaauw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0332-7506","authenticated-orcid":false,"given":"Vasileios","family":"Konstantakos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3122-9858","authenticated-orcid":false,"given":"Eren Can","family":"Ek\u015fi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1165-2189","authenticated-orcid":false,"given":"Sam","family":"Dieltiens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0636-517X","authenticated-orcid":false,"given":"Darina","family":"Abaffyov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2672-7705","authenticated-orcid":false,"given":"Val\u00e9rie","family":"Bercier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5077-5264","authenticated-orcid":false,"given":"Ibrahim I.","family":"Taskiran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert","family":"Hulselmans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1375-4157","authenticated-orcid":false,"given":"Katina","family":"Spanier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Christiaens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0104-4067","authenticated-orcid":false,"given":"Ludo","family":"Van Den Bosch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5085-6985","authenticated-orcid":false,"given":"Lukas","family":"Mahieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8006-0315","authenticated-orcid":false,"given":"Stein","family":"Aerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"3057_CR1","doi-asserted-by":"publisher","unstructured":"Davidson, E. 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