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Praziquantel is the sole recommended drug against Schistosoma mansoni; however, it lacks activity against juvenile forms and cannot prevent reinfection. Thus, there is an urgent need to identify novel therapeutic targets. Long noncoding RNAs (lncRNAs) are known to regulate various biological processes in S. mansoni, including parasite pairing and fertility; therefore, screening for novel lncRNAs could reveal new potential targets. Methods: We compiled all publicly available RNA-seq data from the Sequence Read Archive (SRA) and performed a hierarchical transcriptome assembly using the multi-sample assembler Ry\u016bt\u014d, combined with version 10 of the S. mansoni genome. We applied HOMER for peak-calling and identification of histone marks and used weighted gene co-expression network analysis (WGCNA) to infer putative functions of lncRNAs in sexual dimorphism. Results: Using a robust pipeline, we identified 10,170 novel lncRNA genes comprising 16,990 novel lncRNA transcripts, including 8783 intergenic, 7918 antisense, and 289 intronic lncRNA transcripts. Most (78.7%) have histone regulatory marks (H3K4me3, H3K27me3, H3K27ac, or H4K20me1) near their transcription start sites, indicating potential expression regulation. Comparing male and female samples, we identified 1991 differentially expressed genes (FDR &lt; 5%, |log2FC| \u2265 1.5), including 296 known lncRNAs and 339 novel lncRNAs. WGCNA identified hub lncRNAs within co-expression modules, and Gene Ontology enrichment analyses (FDR \u2264 5%) suggest that these lncRNAs are involved in cell differentiation and morphogenesis pathways. Conclusions: We provide a comprehensive catalog of S. mansoni lncRNAs. These findings offer opportunities to discover potential new therapeutic targets, advancing the future development of anti-schistosome therapies.<\/jats:p>","DOI":"10.3390\/ncrna12020009","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T14:46:31Z","timestamp":1773326791000},"page":"9","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Comprehensive Schistosoma mansoni Hierarchical Transcriptome Assembly Points to Novel lncRNAs Associated with Sexual Dimorphism"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4059-3820","authenticated-orcid":false,"given":"Caio Felipe","family":"Freire","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Ciclo Celular, Instituto Butantan, S\u00e3o Paulo 05503-900, SP, Brazil"},{"name":"Programa Interunidades de P\u00f3s-Gradua\u00e7\u00e3o em Bioinform\u00e1tica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thalles","family":"Souza-Lopes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ciclo Celular, Instituto Butantan, S\u00e3o Paulo 05503-900, SP, Brazil"},{"name":"Programa Interunidades de P\u00f3s-Gradua\u00e7\u00e3o em Bioinform\u00e1tica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4999-5099","authenticated-orcid":false,"given":"Murilo Sena","family":"Amaral","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ciclo Celular, Instituto Butantan, S\u00e3o Paulo 05503-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7036-7305","authenticated-orcid":false,"given":"Ana Carolina","family":"Tahira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ciclo Celular, Instituto Butantan, S\u00e3o Paulo 05503-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6356-2401","authenticated-orcid":false,"given":"Sergio","family":"Verjovski-Almeida","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ciclo Celular, Instituto Butantan, S\u00e3o Paulo 05503-900, SP, Brazil"},{"name":"Departamento de Bioqu\u00edmica, Instituto de Qu\u00edmica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1016\/S0140-6736(13)61949-2","article-title":"Human schistosomiasis","volume":"383","author":"Colley","year":"2014","journal-title":"Lancet"},{"key":"ref_2","unstructured":"WHO (2025, November 15). 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