{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T16:15:42Z","timestamp":1788279342462,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical &amp;amp; Exp Dental Res"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To classify differentially methylated CpG sites in periodontitis based on methylation shift direction and location relative to CpG islands.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Material and Methods<\/jats:title>\n                    <jats:p>\n                      We integrated DNA methylation data from 65 gingival samples (31 periodontitis, 34 healthy) from three GEO datasets. Preprocessing included normalization using R pipelines. Differential DNA methylation analysis was performed with the limma package. CpG sites (adjusted\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) were further evaluated using an exploratory threshold\u2010crossing framework based on group\u2010mean\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2010values (cutoff = 0.5) identifying Control low \u2192 Periodontitis high and Control high \u2192 Periodontitis low shifts, annotated with Illumina 450k references. Top 20 CpG\u2010associated genes were selected by absolute logFC. Gene Ontology (GO) enrichment was conducted using clusterProfiler.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified 164,400 differentially methylated CpG sites, including CpGs exhibiting Control low \u2192 Periodontitis high and Control high \u2192 Periodontitis low shifts, and mapped to gene features. Nearly half of methylation alterations (47.77%) were in OpenSea regions, with additional signals in CpG islands and promoter\u2010proximal regions. GO enrichment analysis revealed that differentially methylated genes in periodontitis were associated with epithelial and organ morphogenesis, including epithelial tube morphogenesis, epithelial cell proliferation, and cell fate commitment. Enriched cellular components were membrane\u2010 and vesicle\u2010associated structures, while molecular functions were transmembrane transporter activity, ion channel activity, and DNA\u2010binding transcription factor\u2013related functions. These findings suggest that DNA methylation alterations in periodontitis are linked to epigenetic regulation of epithelial structure and tissue remodeling, with implications for immune\u2010related cellular processes.<\/jats:p>\n                    <jats:p>\n                      Among the top 20 genes exhibiting \u03b2\u2010threshold\u2013based directionality changes, 13 were significantly enriched in GO terms: 8 in the Control low \u2192 Periodontitis high group (\n                      <jats:italic>DGKA<\/jats:italic>\n                      ,\n                      <jats:italic>CHMP6<\/jats:italic>\n                      ,\n                      <jats:italic>RUNX2<\/jats:italic>\n                      ,\n                      <jats:italic>CDKL1<\/jats:italic>\n                      ,\n                      <jats:italic>SLC6A3<\/jats:italic>\n                      ,\n                      <jats:italic>CFTR<\/jats:italic>\n                      ,\n                      <jats:italic>HLA\u2010C<\/jats:italic>\n                      ,\n                      <jats:italic>LRIG1<\/jats:italic>\n                      ), 5 in the Control high \u2192 Periodontitis low group (\n                      <jats:italic>AP2A2<\/jats:italic>\n                      ,\n                      <jats:italic>PARD3<\/jats:italic>\n                      ,\n                      <jats:italic>PADI2<\/jats:italic>\n                      ,\n                      <jats:italic>FOXK1<\/jats:italic>\n                      ,\n                      <jats:italic>RGS1<\/jats:italic>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides an exploratory, direction\u2010aware summary framework of DNA methylation in periodontitis, highlighting functional changes beyond CpG islands and identifying candidate genes for further functional validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cre2.70312","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T18:20:22Z","timestamp":1773339622000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Alterations Beyond CpG Islands in Periodontitis: In Silico Study of DNA Methylation Data"],"prefix":"10.1002","volume":"12","author":[{"given":"Koki","family":"Yoshida","sequence":"first","affiliation":[{"name":"Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry Health Sciences University of Hokkaido Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5877-205X","authenticated-orcid":false,"given":"Gowri","family":"Sivaramakrishnan","sequence":"additional","affiliation":[{"name":"Bahrain Defence Force Royal Medical Services Riffa Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5186-2645","authenticated-orcid":false,"given":"Farah","family":"Asa'ad","sequence":"additional","affiliation":[{"name":"Department of Oral Biochemistry, Institute of Odontology, Sahlgrenska Academy University of Gothenburg Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1042\/CBI2009\/0019"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/15592294.2015.1006497"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2015.2271"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/prd.12231"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600\u20100757.2012.00450.x"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2025.1505933"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148\u2010021\u201001074\u2010w"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.7b00241"},{"key":"e_1_2_14_10_1","unstructured":"Core Team R. (2024). R: A Language and Environment for Statistical Computing. Vienna Austria: R Foundation for Statistical Computing. Retrieved fromhttps:\/\/www.R\u2010project.org\/."},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/1868\u20107083\u20106\u201015"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010018\u20101588\u20102"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra072067"},{"issue":"4","key":"e_1_2_14_14_1","first-page":"1754","article-title":"The Shifting Landscape of Genetic Alterations Separating Endometriosis and Ovarian Endometrioid Carcinoma","volume":"11","author":"Gaia\u2010Oltean A. I.","year":"2021","journal-title":"American Journal of Cancer Research"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3230"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg816"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010021\u201092607\u2010z"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.38"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u2010981\u201010\u20103233\u20102_6"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.701924"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1214\/16\u2010AOAS920"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7513"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3000"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_2_14_25_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.12.7804"},{"key":"e_1_2_14_26_1","doi-asserted-by":"publisher","DOI":"10.4161\/epi.23062"},{"key":"e_1_2_14_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdsr.2022.06.001"},{"key":"e_1_2_14_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adi7418"},{"key":"e_1_2_14_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010022\u201003664\u20105"},{"key":"e_1_2_14_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcpe.13852"}],"container-title":["Clinical and Experimental Dental Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cre2.70312","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cre2.70312","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cre2.70312","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T15:19:36Z","timestamp":1788275976000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cre2.70312"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,12]]},"references-count":29,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/cre2.70312"],"URL":"https:\/\/doi.org\/10.1002\/cre2.70312","archive":["Portico"],"relation":{},"ISSN":["2057-4347","2057-4347"],"issn-type":[{"value":"2057-4347","type":"print"},{"value":"2057-4347","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,12]]},"assertion":[{"value":"2025-07-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70312"}}