{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T01:32:20Z","timestamp":1772760740358,"version":"3.50.1"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001341","name":"Richard & Susan Smith Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM147254"],"award-info":[{"award-number":["R35GM147254"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["CAREER-MCB-2339464"],"award-info":[{"award-number":["CAREER-MCB-2339464"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Exons within transcripts are traditionally classified as first, internal or last exons, each governed by different regulatory mechanisms. We recently described the widespread usage of \u2018hybrid\u2019 exons that serve as terminal or internal exons in different transcripts. Here, we employ an interpretable deep learning pipeline to dissect the sequence features governing the co-regulation of transcription initiation and splicing in hybrid exons. Using ENCODE data from human tissues, we identified 80\u00a0000 hybrid first-internal exons. These exons often possess a relaxed chromatin state, allowing transcription initiation within the gene body. Interestingly, transcription start sites of hybrid exons are typically centered at the 3\u2032 splice site, suggesting tight coupling between splicing and transcription initiation. We identified two subcategories of hybrid exons: the majority resemble internal exons, maintaining strong 3\u2032 splice sites, while a minority show enrichment in promoter elements, resembling first exons. Diving into the evolution of their sequences, we found that human hybrid exons with orthologous first exons in other species usually gained 3\u2032 splice sites or whole exons upstream, while those with orthologous internal exons often gained promoter elements. Overall, our findings unveil the intricate regulatory landscape of hybrid exons and reveal stronger connections between transcription initiation and RNA splicing than previously acknowledged.<\/jats:p>","DOI":"10.1093\/nar\/gkae1251","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T06:35:17Z","timestamp":1735626917000},"source":"Crossref","is-referenced-by-count":1,"title":["Hybrid exons evolved by coupling transcription initiation and splicing at the nucleotide level"],"prefix":"10.1093","volume":"53","author":[{"given":"Steven\u00a0T","family":"Mick","sequence":"first","affiliation":[{"name":"Biology Department, Boston University , 24 Cummington Ave.,\u00a0 Boston ,\u00a002215,\u00a0","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine\u00a0L","family":"Carroll","sequence":"additional","affiliation":[{"name":"Biology Department, Boston University , 24 Cummington Ave.,\u00a0 Boston ,\u00a002215,\u00a0","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maritere","family":"Uriostegui-Arcos","sequence":"additional","affiliation":[{"name":"Biology Department, Boston University , 24 Cummington Ave.,\u00a0 Boston ,\u00a002215,\u00a0","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4190-5901","authenticated-orcid":false,"given":"Ana","family":"Fiszbein","sequence":"additional","affiliation":[{"name":"Biology Department, Boston University , 24 Cummington Ave.,\u00a0 Boston ,\u00a002215,\u00a0","place":["USA"]},{"name":"Computing & Data Sciences, Boston University , 665 Commonwealth Ave.,\u00a0 Boston ,\u00a002215,\u00a0","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"2025020516033149800_B1","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/nature07509","article-title":"Alternative isoform regulation in human tissue transcriptomes","volume":"456","author":"Wang","year":"2008","journal-title":"Nature"},{"key":"2025020516033149800_B2","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1038\/s41587-022-01231-3","article-title":"Single-nuclei isoform RNA sequencing unlocks barcoded exon connectivity in frozen brain tissue","volume":"40","author":"Hardwick","year":"2022","journal-title":"Nat. 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