{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:17:05Z","timestamp":1788254225233,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Cis-regulatory elements (CREs) help mediate cell-type-selective gene expression, yet sequence-to-activity models are rarely converted into compact, experimentally tractable variant panels that retain natural regulatory scaffolds. We developed SafeEdit-CRE to select minimal edits that preserve cross-model specificity while reducing predictive uncertainty, yielding an auditable CRE variant library for reporter-screening prioritization. Methods: SafeEdit-CRE combines the published Malinois sequence\u2013activity predictor with an architecture-distinct reviewer ensemble, validation-calibrated uncertainty, sequence-domain controls, and constrained beam search. Natural 200 nt CREs were edited under fixed substitution budgets of 1, 5, 10, or 20 nucleotides and evaluated by a separately trained multi-kernel ensemble kept entirely separate from candidate generation. Results: Across 600 held-out CRE parents in K562, HepG2, and SK-N-SH cells, SafeEdit-CRE achieved a mean cross-model specificity-margin gain of 0.877 versus 0.822 for greedy editing (paired difference 0.055; 95% CI 0.040\u20130.071). Relative to a compute-matched primary-model beam, SafeEdit-CRE yielded a similar cross-model specificity-margin gain (difference \u22120.004; 95% CI \u22120.011\u20130.004) with lower ensemble uncertainty (0.314 vs. 0.335). In a locked 90-parent benchmark, 60.6% of designs passed all nine prespecified sequence and model-agreement checks, compared with 38.8% for greedy and 13.1% for random substitution (paired difference 21.8 percentage points; 95% CI 18.3\u201325.3). Conclusions: SafeEdit-CRE reduced 3240 designs to 74 Tier A computational candidates prioritized for reporter screening across three cell types and four edit budgets. By separating search from cross-model audit and enforcing explicit edit budgets and sequence\u2013domain safeguards, the framework provides a reproducible and auditable approach to computational CRE prioritization, regulatory-grammar studies, and synthetic regulatory-element design.<\/jats:p>","DOI":"10.3390\/genes17091062","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:31:13Z","timestamp":1788251473000},"page":"1062","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cross-Model Uncertainty-Aware Minimal Editing of Cis-Regulatory Elements for Cell-Type-Selective Design"],"prefix":"10.3390","volume":"17","author":[{"given":"Angran","family":"Xia","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Shaanxi Normal University, 620 West Chang\u2019an Avenue, Chang\u2019an District, Xi\u2019an 710119, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changwei","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Shaanxi Normal University, 620 West Chang\u2019an Avenue, Chang\u2019an District, Xi\u2019an 710119, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yemao","family":"Xia","sequence":"additional","affiliation":[{"name":"College of Science, Nanjing Forestry University, 159 Longpan Road, Xuanwu District, Nanjing 210037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/nrg1315","article-title":"Applied bioinformatics for the identification of regulatory elements","volume":"5","author":"Wasserman","year":"2004","journal-title":"Nat. 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