{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T10:50:37Z","timestamp":1774263037518,"version":"3.50.1"},"reference-count":73,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T00:00:00Z","timestamp":1774051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["T2222007"],"award-info":[{"award-number":["T2222007"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by genetic heterogeneity. Post-transcriptional regulation\u2014particularly alternative polyadenylation (APA)\u2014plays a critical role in the pathogenesis of ASD. APA controls mRNA stability, translational efficiency, and subcellular localization through modulating the length of the 3\u2032 untranslated region of mRNA. APA profiling can uncover functionally relevant post-transcriptional alterations often missed by conventional gene expression analyses. However, current ASD analyses still largely rely on differential gene expression or individual APA event detection, which ignores the collective explanatory power of ASD risk genes or co-dysregulated functional gene modules within specific cell types. In this study, we present an integrative computational framework that combines matrix factorization and machine learning to identify ASD-associated gene modules driven by APA and to predict cell-type-specific ASD-related cells. Applied to human brain single-nucleus RNA sequencing (snRNA-seq) data, our approach systematically uncovers APA regulatory patterns that are specific to cell type, brain region, and sex in ASD. The identified APA modules are significantly enriched in pathways related to synaptic function, neurodevelopment, and immune response, with the strongest signals observed in excitatory neurons of the prefrontal cortex. Using APA genes from these modules as features, we built a classification model that effectively distinguishes ASD cells from normal cells. Moreover, we found that integrating APA with gene expression\u2014two complementary modalities\u2014substantially improves prediction accuracy, underscoring APA as an independent and biologically informative regulatory layer. Our work delineates a high-resolution APA regulatory landscape in ASD, offering novel insights and potential therapeutic avenues beyond transcriptional abundance.<\/jats:p>","DOI":"10.3390\/ijms27062849","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T09:48:42Z","timestamp":1774259322000},"page":"2849","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-Cell Gene Module Inference Reveals Alternative Polyadenylation Dynamics Associated with Autism"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6754-6458","authenticated-orcid":false,"given":"Fei","family":"Liu","sequence":"first","affiliation":[{"name":"Cancer Institute, Suzhou Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haoran","family":"Yang","sequence":"additional","affiliation":[{"name":"Cancer Institute, Suzhou Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0356-7785","authenticated-orcid":false,"given":"Xiaohui","family":"Wu","sequence":"additional","affiliation":[{"name":"Cancer Institute, Suzhou Medical College, Soochow University, Suzhou 215000, China"},{"name":"Suzhou Key Laboratory of Pathogen Bioscience and Anti-Infective Medicine, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College, Soochow University, Suzhou 215000, China"},{"name":"Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215000, China"},{"name":"Pediatric Hematology & Oncology Key Laboratory of Higher Education Institutions in Jiangsu Province, Suzhou 215000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.cell.2019.07.037","article-title":"Getting to the Cores of Autism","volume":"178","author":"Iakoucheva","year":"2019","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41572-019-0138-4","article-title":"Autism spectrum disorder","volume":"6","author":"Lord","year":"2020","journal-title":"Nat. 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