{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:09:50Z","timestamp":1788930590469,"version":"build-2803163510"},"reference-count":35,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombotic and inflammatory manifestations whose molecular regulatory mechanisms remain incompletely understood. Long non-coding RNAs (lncRNAs) and N6-methyladenosine (m6A)-related regulation are increasingly recognized as components of immune gene regulation, but their involvement in APS remains poorly characterized. This study investigated BRD3OS (LINC00094) expression in APS and explored its molecular and predicted structural context in relation to m6A-associated regulation. An exploratory case\u2013control study was conducted using an initial lncRNA PCR-array discovery cohort followed by targeted RT-qPCR validation in an independent cohort. Candidate prioritization incorporated multiple expression and technical features and was evaluated through sensitivity analyses. BRD3OS expression, selected m6A regulators (METTL3, METTL14, WTAP, and FTO), inflammatory mediators, and global m6A abundance in total peripheral blood mononuclear cell (PBMC) RNA were evaluated. Bioinformatic network analysis was used to contextualize BRD3OS within APS- and m6A-related molecular systems. RNAfold and RNAplfold were used to characterize the predicted structural context and accessibility of DRACH consensus motifs, with additional analyses evaluating fragment-boundary and composite-score robustness. BRD3OS was significantly downregulated in PBMCs from patients with APS in the independent validation cohort. METTL3, METTL14, and WTAP expression was also reduced, whereas global m6A levels in total PBMC RNA were increased. These observations indicate concurrent alterations in BRD3OS expression and the broader m6A-related molecular environment but do not establish transcript-specific methylation of BRD3OS. Bioinformatic network analysis placed BRD3OS within predicted RNA-centered regulatory relationships relevant to APS. DRACH motifs exhibited heterogeneous predicted structural accessibility, with unpaired structural environments showing greater RNAplfold-derived accessibility than paired regions. Quantitative accessibility estimates were highly concordant across overlapping transcript fragments, although sensitivity analyses indicated that the identity of individual highest-ranked candidates depended on the weighting scheme. BRD3OS downregulation represents a reproducible molecular finding in APS. Concurrent alterations in global m6A abundance and selected m6A regulators suggest broader epitranscriptomic dysregulation; however, these measurements cannot establish m6A modification of BRD3OS or a causal relationship between these observations. Structural and network analyses therefore provide a hypothesis-generating framework for prioritizing candidate regions and interactions for future transcript-specific methylation mapping and functional validation.<\/jats:p>","DOI":"10.3390\/biom16091263","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T15:08:43Z","timestamp":1788275323000},"page":"1263","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["BRD3OS Dysregulation in Antiphospholipid Syndrome: Integrative Network and RNA Structural Analysis of m6A-Related Candidate Regions"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7365-9023","authenticated-orcid":false,"given":"Carlos A.","family":"Guzm\u00e1n-Mart\u00edn","sequence":"first","affiliation":[{"name":"Doctorado en Ciencias Biol\u00f3gicas y de la Salud, Universidad Aut\u00f3noma Metropolitana, Mexico City 04960, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6467-6638","authenticated-orcid":false,"given":"Yaneli","family":"Ju\u00e1rez-Vicu\u00f1a","sequence":"additional","affiliation":[{"name":"Departamento de Inmunolog\u00eda, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5806-3675","authenticated-orcid":false,"given":"Rafael","family":"Bojalil","sequence":"additional","affiliation":[{"name":"Departamento de Atenci\u00f3n a la Salud, Universidad Aut\u00f3noma Metropolitana, Mexico City 04960, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"Aranda-Cano","sequence":"additional","affiliation":[{"name":"Departamento de Reumatolog\u00eda, Hospital Central Militar, Secretar\u00eda de la Defensa Nacional, Mexico City 11200, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2883-0028","authenticated-orcid":false,"given":"Mario","family":"Pe\u00f1a-Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamnia Q.","family":"Alvarez-Alvarez","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6503-694X","authenticated-orcid":false,"given":"Fengyang","family":"Huang","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Obesidad y Asma, Hospital Infantil de M\u00e9xico Federico G\u00f3mez, Mexico City 06720, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7541-8773","authenticated-orcid":false,"given":"Javier","family":"Gonz\u00e1lez-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular, Facultad de Enfermer\u00eda, Universidad Aut\u00f3noma de Baja California, Campus Mexicali, Mexicali 21100, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7439-2615","authenticated-orcid":false,"given":"Laura Aline","family":"Mart\u00ednez-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Departamento de Reumatolog\u00eda, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6556-1632","authenticated-orcid":false,"given":"Fausto","family":"S\u00e1nchez-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1538-7836.2006.01753.x","article-title":"International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Syndrome (APS)","volume":"4","author":"Miyakis","year":"2006","journal-title":"J. Thromb. Haemost."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1136\/ard-2023-224609","article-title":"2023 ACR\/EULAR Antiphospholipid Syndrome Classification Criteria","volume":"82","author":"Barbhaiya","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1111\/jth.15082","article-title":"Antiphospholipid Syndrome: Complement Activation, Complement Gene Mutations, and Therapeutic Implications","volume":"19","author":"Chaturvedi","year":"2021","journal-title":"J. Thromb. Haemost."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e069717","DOI":"10.1136\/bmj-2021-069717","article-title":"Antiphospholipid Syndrome: Advances in Diagnosis, Pathogenesis, and Management","volume":"380","author":"Knight","year":"2023","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Feng, W., Qiao, J., Tan, Y., Liu, Q., Wang, Q., Yang, B., Yang, S., and Cui, L. (2024). Interaction of Antiphospholipid Antibodies with Endothelial Cells in Antiphospholipid Syndrome. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1361519"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/s41580-022-00566-8","article-title":"Long Non-Coding RNAs: Definitions, Functions, Challenges and Recommendations","volume":"24","author":"Mattick","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/s41580-020-00315-9","article-title":"Gene Regulation by Long Non-Coding RNAs and Its Biological Functions","volume":"22","author":"Statello","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lodde, V., Murgia, G., Simula, E.R., Steri, M., Floris, M., and Idda, M.L. (2020). Long Noncoding RNAs and Circular RNAs in Autoimmune Diseases. Biomolecules, 10.","DOI":"10.3390\/biom10071044"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1007\/s11033-022-08080-y","article-title":"lncRNAs Dysregulation in Monocytes from Primary Antiphospholipid Syndrome Patients: A Bioinformatic and an Experimental Proof-of-Concept Approach","volume":"50","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_10","unstructured":"Ensembl (2026, March 31). Gene: BRD3OS (ENSG00000235106)\u2014Summary\u2014Homo sapiens\u2014Ensembl Genome Browser 115. Available online: https:\/\/www.ensembl.org\/Homo_sapiens\/Gene\/Summary?g=ENSG00000235106."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Piipponen, M., Riihil\u00e4, P., Knuutila, J.S., Kallajoki, M., K\u00e4h\u00e4ri, V.M., and Nissinen, L. (2022). Super Enhancer-Regulated LINC00094 (SERLOC) Upregulates the Expression of MMP-1 and MMP-13 and Promotes Invasion of Cutaneous Squamous Cell Carcinoma. Cancers, 14.","DOI":"10.3390\/cancers14163980"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3280","DOI":"10.1111\/jcmm.14214","article-title":"The Role of LINC00094\/miR-224-5p (miR-497-5p)\/Endophilin-1 Axis in Memantine-Mediated Protective Effects on Blood\u2013Brain Barrier in AD Microenvironment","volume":"23","author":"Zhu","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1146\/annurev-cellbio-100616-060758","article-title":"Rethinking m6A Readers, Writers, and Erasers","volume":"33","author":"Meyer","year":"2017","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.molcel.2023.01.006","article-title":"RNA m6A Methylation across the Transcriptome","volume":"83","author":"Sendinc","year":"2023","journal-title":"Mol. Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/s41590-018-0275-z","article-title":"m6A Modification Controls the Innate Immune Response to Infection by Targeting Type I Interferons","volume":"20","author":"Winkler","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/s41420-022-01113-2","article-title":"The Role of N6-Methyladenosine-Modified Non-Coding RNAs in the Pathological Process of Human Cancer","volume":"8","author":"Luo","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1016\/j.molcel.2022.05.029","article-title":"Hidden Codes in mRNA: Control of Gene Expression by m6A","volume":"82","author":"Murakami","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1007\/s11095-026-04087-3","article-title":"Regulatory Roles of Long Non-Coding RNAs in Methotrexate Pharmacology: Mechanistic and Translational Insights","volume":"43","author":"Bojalil","year":"2026","journal-title":"Pharm. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1038\/s41580-019-0168-5","article-title":"Reading, Writing and Erasing mRNA Methylation","volume":"20","author":"Zaccara","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41590-020-0650-4","article-title":"The RNA Modification N6-Methyladenosine as a Novel Regulator of the Immune System","volume":"21","author":"Shulman","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"D326","DOI":"10.1093\/nar\/gkab997","article-title":"RNAInter v4.0: RNA Interactome Repository with Redefined Confidence Scoring System and Improved Accessibility","volume":"50","author":"Kang","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D833","DOI":"10.1093\/nar\/gkw943","article-title":"DisGeNET: A Comprehensive Platform Integrating Information on Human Disease-Associated Genes and Variants","volume":"45","author":"Bravo","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1093\/nar\/gkae883","article-title":"Comparative Toxicogenomics Database\u2019s 20th Anniversary: Update 2025","volume":"53","author":"Davis","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.it.2014.07.005","article-title":"Long Non-Coding RNAs in the Regulation of the Immune Response","volume":"35","author":"Heward","year":"2014","journal-title":"Trends Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/nature14234","article-title":"N6-Methyladenosine-Dependent RNA Structural Switches Regulate RNA\u2013Protein Interactions","volume":"518","author":"Liu","year":"2015","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nature11112","article-title":"Topology of the Human and Mouse m6A RNA Methylomes Revealed by m6A-Seq","volume":"485","author":"Dominissini","year":"2012","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1016\/j.cell.2012.05.003","article-title":"Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3\u2032 UTRs and near Stop Codons","volume":"149","author":"Meyer","year":"2012","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1093\/bioinformatics\/btk014","article-title":"Local RNA Base Pairing Probabilities in Large Sequences","volume":"22","author":"Bernhart","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1748-7188-6-26","article-title":"ViennaRNA Package 2.0","volume":"6","author":"Lorenz","year":"2011","journal-title":"Algorithms Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1007\/s11033-026-12270-3","article-title":"A Novel Method for the Identification and Quantification of N6-Methyladenosine Motifs in RNA Transcripts","volume":"53","author":"Choudhari","year":"2026","journal-title":"Mol. Biol. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.molcel.2016.01.012","article-title":"Nuclear m6A Reader YTHDC1 Regulates mRNA Splicing","volume":"61","author":"Xiao","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_32","first-page":"16","article-title":"Proof-of-Concept Evidence for lncRNA NRIR Downregulation in Antiphospholipid Syndrome and Its Obstetric Subtype","volume":"3","year":"2026","journal-title":"Clin. Innov. Health Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/nmeth.3453","article-title":"Single-Nucleotide-Resolution Mapping of m6A and m6Am throughout the Transcriptome","volume":"12","author":"Linder","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nmeth.4577","article-title":"Highly Parallel Direct RNA Sequencing on an Array of Nanopores","volume":"15","author":"Garalde","year":"2018","journal-title":"Nat. Methods"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4079","DOI":"10.1038\/s41467-019-11713-9","article-title":"Accurate Detection of m6A RNA Modifications in Native RNA Sequences","volume":"10","author":"Liu","year":"2019","journal-title":"Nat. Commun."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/9\/1263\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T04:29:59Z","timestamp":1788928199000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/9\/1263"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":35,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["biom16091263"],"URL":"https:\/\/doi.org\/10.3390\/biom16091263","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]}}}