{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:39:31Z","timestamp":1791405571239,"version":"4.3.3"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"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","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Growing evidence demonstrated that m6A modification in cardiovascular diseases. However, how it is involved in the intracranial aneurysm (IA) is still unclear. This study aimed to identify the role of m6A modification in IA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Three datasets downloaded from the Gene Expression Omnibus (GEO) database were used, including GSE122897, GSE15629, and GSE3679. The landscapes of 24 m6A regulators were depicted using the STRING database, Pearson\u2019s correlation analysis, and Wilcoxon test. The targets of differentially expressed m6A (DEm6A) were predicted in the m6A2Target database and the modification m6A sites of hub targets were identified in SRAMP online tool. A diagnostic model based on DEm6A was constructed and verified in training and test databases. A consensus clustering algorithm was performed to classify IA patients into distinct m6A-related clusters. Functional analyses including gene ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set variation analysis, and gene set enrichment analysis analyses were conducted to elucidate the underlying mechanisms. ssGSEA algorithm was performed to uncover the immune characteristics. A PCA method was adopted to quantify the m6A score.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Nine DEm6A (IGF2BP1, IGF2BP3, YTHDF2, ZNF217, RBM15, YTHDF3, YTHDC1, FTO, and LRPPRC) significantly differed between IA and controls. Biological annotations showed that immune-related pathways (such as complement activation, inflammatory response, and interleukin signaling) and apoptosis were more enriched in IAs than in controls. Immune analyses indicate that the abundance of immune cells, immune responses, and HLA gene expression were elevated in IA samples than in controls. PCA results showed that IA has a lower m6A score than controls. An immune\/apoptosis-related network modified by DEm6A was constructed. The m6A sites of six hub targets (CDK1, ASPM, AURKB, BUB1B, MKI67, and TPX2) were predicted with very high confidence. A diagnostic model with four genes (LRPPRC, YTHDF3, IGF2BP1, and ZNF217) was constructed and verified. Two m6A modification subtypes were identified with unsupervised cluster analysis. Immune infiltration analysis revealed that cluster 1 had higher immune activation than cluster 2. Further study showed that cluster 1 had a larger proportion of ruptured IAs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The m6A modification may shape the IAs microenvironment and participates in the formation and rupture of IAs by regulating immune infiltration.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2022.973258","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T11:44:10Z","timestamp":1660218250000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Novel insight into m6A regulator-mediated methylation modification patterns and immune characteristics in intracranial aneurysm"],"prefix":"10.3389","volume":"14","author":[{"given":"Shifu","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1038\/s41588-020-00725-7","article-title":"Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.","volume":"52","author":"Bakker","year":"2020","journal-title":"Nat. Genet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1007\/s12026-014-8516-1","article-title":"ImmPort: Disseminating data to the public for the future of immunology.","volume":"58","author":"Bhattacharya","year":"2014","journal-title":"Immunol. Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1659","DOI":"10.1038\/jcbfm.2012.84","article-title":"Biology of intracranial aneurysms: Role of inflammation.","volume":"32","author":"Chalouhi","year":"2012","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B4","doi-asserted-by":"publisher","first-page":"3613","DOI":"10.1161\/strokeaha.113.002390","article-title":"Review of cerebral aneurysm formation, growth, and rupture.","volume":"44","author":"Chalouhi","year":"2013","journal-title":"Stroke."},{"key":"B5","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1080\/14737159.2022.2049246","article-title":"Role of N6-methyladenosine modification in pathogenesis of ischemic stroke.","volume":"22","author":"Chang","year":"2022","journal-title":"Expert Rev. Mol. Diagn."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaa055","article-title":"M6A2Target: A comprehensive database for targets of m6A writers, erasers and readers.","volume":"22","author":"Deng","year":"2021","journal-title":"Brief. Bioinformatics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"3971","DOI":"10.1073\/pnas.71.10.3971","article-title":"Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells.","volume":"71","author":"Desrosiers","year":"1974","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B8","doi-asserted-by":"publisher","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":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.731810","article-title":"N6-Methyladenosine methyltransferase METTL3 promotes angiogenesis and atherosclerosis by upregulating the JAK2\/STAT3 pathway via m6A reader IGF2BP1.","volume":"9","author":"Dong","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1038\/nrneurol.2016.150","article-title":"Unruptured intracranial aneurysms: Development, rupture and preventive management.","volume":"12","author":"Etminan","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.781207","article-title":"EGR1 and KLF4 as diagnostic markers for abdominal aortic aneurysm and associated with immune infiltration.","volume":"9","author":"Guo","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1007\/s12975-013-0313-y","article-title":"Inflammation and cerebral aneurysms.","volume":"5","author":"Hosaka","year":"2014","journal-title":"Transl. Stroke Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1164\/rccm.202009-3419OC","article-title":"YTHDF1 regulates pulmonary hypertension through translational control of MAGED1.","volume":"203","author":"Hu","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-018-0628-y","article-title":"Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in cancer.","volume":"11","author":"Huang","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"4245","DOI":"10.2147\/jir.S327152","article-title":"Expression pattern and clinical value of key m6A RNA modification regulators in abdominal aortic aneurysm.","volume":"14","author":"Li","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection.","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.22994","article-title":"Silencing of IGF2BP1 restrains ox-LDL-induced lipid accumulation and inflammation by reducing RUNX1 expression and promoting autophagy in macrophages.","volume":"36","author":"Liu","year":"2022","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2022.146250","article-title":"Comprehensive analysis of m(6)A regulator-based methylation modification patterns characterized by distinct immune profiles in colon adenocarcinomas.","volume":"821","author":"Liu","year":"2022","journal-title":"Gene"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.52.2.291-a","article-title":"Intracranial aneurysm and HLA-DR2.","volume":"52","author":"Lye","year":"1989","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1136\/jnnp.52.10.1197","article-title":"Are HLA antigens implicated in the pathogenesis of non-haemorrhagic deterioration following aneurysmal subarachnoid haemorrhage.","volume":"52","author":"Lye","year":"1989","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2020.592550","article-title":"Vascular smooth muscle FTO promotes aortic dissecting aneurysms via m6A modification of Klf5.","volume":"7","author":"Ma","year":"2020","journal-title":"Front. Cardiovasc. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1016\/j.cell.2012.05.003","article-title":"Comprehensive analysis of mRNA methylation reveals enrichment in 3\u2019 UTRs and near stop codons.","volume":"149","author":"Meyer","year":"2012","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1161\/atvbaha.117.309795","article-title":"Extracellular vesicles secreted by atherogenic macrophages transfer microRNA to inhibit cell migration.","volume":"38","author":"Nguyen","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1111\/j.1399-0039.1986.tb00478.x","article-title":"HLA antigens and complement types in patients with intracranial saccular aneurysms.","volume":"28","author":"Ostergaard","year":"1986","journal-title":"Tissue Antigens"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.3171\/jns.2004.101.6.1018","article-title":"Role of apoptosis in intracranial aneurysm rupture.","volume":"101","author":"Pentimalli","year":"2004","journal-title":"J. Neurosurg."},{"key":"B26","doi-asserted-by":"publisher","first-page":"226","DOI":"10.3238\/arztebl.2017.0226","article-title":"Aneurysmal subarachnoid hemorrhage.","volume":"114","author":"Petridis","year":"2017","journal-title":"Dtsch. Arztebl. Int."},{"key":"B27","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1002\/hep.30149","article-title":"Negative regulation of mitochondrial antiviral signaling protein-mediated antiviral signaling by the mitochondrial protein LRPPRC during hepatitis C virus infection.","volume":"69","author":"Refolo","year":"2019","journal-title":"Hepatology"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies.","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.51.6.883","article-title":"Intracranial aneurysm and HLA-DR2.","volume":"51","author":"Schievink","year":"1988","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B30","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/j.molcel.2019.04.025","article-title":"Where, when, and how: Context-dependent functions of RNA methylation writers, readers, and erasers.","volume":"74","author":"Shi","year":"2019","journal-title":"Mol. Cell"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.756483","article-title":"Comprehensive analysis of N6-methyladenosine RNA methylation regulators expression identify distinct molecular subtypes of myocardial infarction.","volume":"9","author":"Shi","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/s41590-020-0650-4","article-title":"The RNA modification N(6)-methyladenosine as a novel regulator of the immune system.","volume":"21","author":"Shulman","year":"2020","journal-title":"Nat. Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1093\/jnci\/djj052","article-title":"Gene expression profiling in breast cancer: Understanding the molecular basis of histologic grade to improve prognosis.","volume":"98","author":"Sotiriou","year":"2006","journal-title":"J. Natl. Cancer Inst."},{"key":"B34","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/labinvest.2009.133","article-title":"Complement system becomes activated by the classical pathway in intracranial aneurysm walls.","volume":"90","author":"Tulamo","year":"2010","journal-title":"Lab. Invest."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1227\/01.Neu.0000245598.84698.26","article-title":"Complement activation associates with saccular cerebral artery aneurysm wall degeneration and rupture.","volume":"59","author":"Tulamo","year":"2006","journal-title":"Neurosurgery"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1093\/bioinformatics\/btq170","article-title":"ConsensusClusterPlus: A class discovery tool with confidence assessments and item tracking.","volume":"26","author":"Wilkerson","year":"2010","journal-title":"Bioinformatics"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1016\/j.ymthe.2020.08.010","article-title":"m(6)A RNA methylation in cardiovascular diseases.","volume":"28","author":"Wu","year":"2020","journal-title":"Mol. Ther."},{"key":"B38","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/s41422-018-0040-8","article-title":"Dynamic transcriptomic m(6)A decoration: Writers, erasers, readers and functions in RNA metabolism.","volume":"28","author":"Yang","year":"2018","journal-title":"Cell Res."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21594-6","article-title":"METTL3-dependent m(6)A modification programs T follicular helper cell differentiation.","volume":"12","author":"Yao","year":"2021","journal-title":"Nat. Commun."},{"key":"B40","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1089\/dna.2015.3105","article-title":"Dysregulation of CD4(+) T cell subsets in intracranial aneurysm.","volume":"35","author":"Zhang","year":"2016","journal-title":"DNA Cell Biol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1073\/pnas.1812536116","article-title":"RNA-binding protein YTHDF3 suppresses interferon-dependent antiviral responses by promoting FOXO3 translation.","volume":"116","author":"Zhang","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B42","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.omtn.2020.06.005","article-title":"METTL3 induces AAA development and progression by modulating N6-methyladenosine-dependent primary miR34a processing.","volume":"21","author":"Zhong","year":"2020","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg0470","article-title":"m(6)A demethylase ALKBH5 controls CD4+ T cell pathogenicity and promotes autoimmunity.","volume":"7","author":"Zhou","year":"2021","journal-title":"Sci. Adv."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw104","article-title":"SRAMP: Prediction of mammalian N6-methyladenosine (m6A) sites based on sequence-derived features.","volume":"44","author":"Zhou","year":"2016","journal-title":"Nucleic Acids Res."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.973258\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T11:44:14Z","timestamp":1660218254000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.973258\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,11]]},"references-count":44,"alternative-id":["10.3389\/fnagi.2022.973258"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2022.973258","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,11]]},"article-number":"973258"}}