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However, accurately predicting enhancer\u2013gene regulatory interactions from single-cell datasets has been challenging. Here we introduce a family of classification models, scE2G, to predict enhancer\u2013gene regulation. These models use features from single-cell assay for transposase-accessible chromatin with sequencing (ATAC-seq) or multiomic RNA and ATAC-seq data, and are trained on a CRISPR perturbation dataset including &gt;10,000 evaluated element\u2013gene pairs. We benchmark scE2G models against CRISPR perturbations, fine-mapped expression quantitative trait loci and genome-wide association study variant\u2013gene associations and demonstrate state-of-the-art performance at prediction tasks across several cell types and categories of perturbations. We apply scE2G to build maps of enhancer\u2013gene regulatory interactions in heterogeneous tissues and interpret noncoding variants associated with complex traits, nominating regulatory interactions linking\n                    <jats:italic>INPP4B<\/jats:italic>\n                    and\n                    <jats:italic>IL15<\/jats:italic>\n                    to lymphocyte count. The scE2G models will enable accurate mapping of enhancer\u2013gene regulatory interactions across thousands of human cell types.\n                  <\/jats:p>","DOI":"10.1038\/s41588-026-02695-8","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T09:04:06Z","timestamp":1785747846000},"page":"1941-1952","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mapping enhancer\u2013gene regulatory interactions from single-cell data"],"prefix":"10.1038","volume":"58","author":[{"given":"Maya U.","family":"Sheth","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6649-0378","authenticated-orcid":false,"given":"Wei-Lin","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8297-4279","authenticated-orcid":false,"given":"X. 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