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These are postulated to be single-stranded in order to be functional, yet knowledge of secondary structural features that regulate the exposure of exonic splicing motifs across the transcriptome is not currently available. Using transcriptome-wide RNA structural information we show that retained introns in mouse are commonly flanked by a short (\u227270 nucleotide), highly base-paired segment upstream and a predominantly single-stranded exonic segment downstream. Splicing assays with select pre-mRNA substrates demonstrate that loops immediately upstream of the introns contain pre-mRNA-specific splicing enhancers, the substitution or hybridization of which impedes splicing. Additionally, the exonic segments flanking the retained introns appeared to be more enriched in a previously identified set of hexameric exonic splicing enhancer (ESE) sequences compared to their spliced counterparts, suggesting that base-pairing in the exonic segments upstream of retained introns could be a means for occlusion of ESEs. The upstream exonic loops of the test substrate promoted recruitment of splicing factors and consequent pre-mRNA structural remodeling, leading up to assembly of the early spliceosome. These results suggest that disruption of exonic stem\u2013loop structures immediately upstream (but not downstream) of the introns regulate alternative splicing events, likely through modulating accessibility of splicing factors.<\/jats:p>","DOI":"10.1093\/nar\/gkaa358","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T07:09:35Z","timestamp":1588057775000},"page":"6294-6309","source":"Crossref","is-referenced-by-count":28,"title":["Structural disruption of exonic stem\u2013loops immediately upstream of the intron regulates mammalian splicing"],"prefix":"10.1093","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1574-2309","authenticated-orcid":false,"given":"Kaushik","family":"Saha","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0375, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6712-0101","authenticated-orcid":false,"given":"Whitney","family":"England","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of California Irvine, 147 Bison Modular, Building 515, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4948-8743","authenticated-orcid":false,"given":"Mike Minh","family":"Fernandez","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0375, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tapan","family":"Biswas","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0375, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert C","family":"Spitale","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of California Irvine, 147 Bison Modular, Building 515, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6311-7351","authenticated-orcid":false,"given":"Gourisankar","family":"Ghosh","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0375, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,5,13]]},"reference":[{"key":"2020061304435774100_B1","doi-asserted-by":"crossref","first-page":"a003707","DOI":"10.1101\/cshperspect.a003707","article-title":"Spliceosome structure and function","volume":"3","author":"Will","year":"2011","journal-title":"Cold Spring Harb. 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