{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:42:28Z","timestamp":1760146948460,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP23ek0109497","22H04925 [PAGS]","21H02476","22K19269","23K21309","24K21987"],"award-info":[{"award-number":["JP23ek0109497","22H04925 [PAGS]","21H02476","22K19269","23K21309","24K21987"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"JSPS KAKENHI","award":["JP23ek0109497","22H04925 [PAGS]","21H02476","22K19269","23K21309","24K21987"],"award-info":[{"award-number":["JP23ek0109497","22H04925 [PAGS]","21H02476","22K19269","23K21309","24K21987"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alternative splicing is essential for the generation of various protein isoforms that are involved in cell differentiation and tissue development. In addition to internal coding exons, alternative splicing affects the exons with translation initiation codons; however, little is known about these exons. Here, we performed a systematic classification of human alternative exons using coding information. The analysis showed that more than 5% of cassette exons contain translation initiation codons (alternatively skipped exons harboring a 5\u2032 untranslated region and coding region, 5UC-ASEs) although their skipping causes the deletion of translation initiation sites essential for protein synthesis. The splicing of 5UC-ASEs is under the repressive control of MATR3, a DNA\/RNA-binding protein associated with neurodegeneration, and is distinctly regulated particularly in the human brain, muscle, and testis. Interestingly, MATR3 represses its own translation by skipping a 5UC-ASE in MATR3 to autoregulate its expression level. 5UC-ASEs are larger than other types of alternative exons. Furthermore, evolutionary analysis revealed that 5UC-ASEs have already appeared in cartilaginous fishes, have increased in amphibians, and are concentrated in the genes involved in transcription in mammals. Taken together, our analysis identified a unique set of alternative exons, 5UC-ASEs, that have evolutionarily acquired a repression mechanism for gene expression through association with MATR3.<\/jats:p>","DOI":"10.3390\/cells14010011","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T19:33:07Z","timestamp":1735241587000},"page":"11","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evolutionarily Developed Alternatively Spliced Exons Containing Translation Initiation Sites"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5367-5608","authenticated-orcid":false,"given":"Jun-ichi","family":"Takeda","sequence":"first","affiliation":[{"name":"Center for One Medicine Innovative Translational Research (COMIT), Institute for Advanced Study, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaaki","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan"},{"name":"Academia-Industry Collaboration Platform for Cultivating Medical AI Leaders (AI-MAILs), Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6437-2853","authenticated-orcid":false,"given":"Akio","family":"Masuda","sequence":"additional","affiliation":[{"name":"Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1126\/science.1058040","article-title":"The sequence of the human genome","volume":"291","author":"Venter","year":"2001","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nature11233","article-title":"Landscape of transcription in human cells","volume":"489","author":"Djebali","year":"2012","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"ENCODE Project Consortium (2012). 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