{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T23:03:41Z","timestamp":1790291021901,"version":"4.1.0"},"reference-count":87,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T00:00:00Z","timestamp":1626652800000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81872274"],"award-info":[{"award-number":["81872274"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cervical cancer (CC) is the second leading cause of cancer death among women worldwide. Epigenetic regulation of gene expression through DNA methylation and hydroxymethylation plays a pivotal role during tumorigenesis. In this study, to analyze the epigenomic landscape and identify potential biomarkers for CCs, we selected a series of samples from normal to cervical intra\u2010epithelial neoplasia (CINs) to CCs and performed an integrative analysis of whole\u2010genome bisulfite sequencing (WGBS\u2010seq), oxidative WGBS, RNA\u2010seq, and external histone modifications profiling data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the development and progression of CC, there were genome\u2010wide hypo\u2010methylation and hypo\u2010hydroxymethylation, accompanied by local hyper\u2010methylation and hyper\u2010hydroxymethylation. Hydroxymethylation prefers to distribute in the CpG islands and CpG shores, as displayed a trend of gradual decline from health to CIN2, while a trend of increase from CIN3 to CC. The differentially methylated and hydroxymethylated region\u2010associated genes both enriched in Hippo and other cancer\u2010related signaling pathways that drive cervical carcinogenesis. Furthermore, we identified eight novel differentially methylated\/hydroxymethylated\u2010associated genes (\n                      <jats:italic>DES, MAL, MTIF2, PIP5K1A, RPS6KA6, ANGEL2, MPP<\/jats:italic>\n                      , and\n                      <jats:italic>PAPSS2<\/jats:italic>\n                      ) significantly correlated with the overall survival of CC. In addition, no any correlation was observed between methylation or hydroxymethylation levels and somatic copy number variations in CINs and CCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our current study systematically delineates the map of methylome and hydroxymethylome from CINs to CC, and some differentially methylated\/hydroxymethylated\u2010associated genes can be used as the potential epigenetic biomarkers in CC prognosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.498","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T09:30:41Z","timestamp":1626687041000},"source":"Crossref","is-referenced-by-count":22,"title":["An epigenomic landscape of cervical intraepithelial neoplasia and cervical cancer using single\u2010base resolution methylome and hydroxymethylome"],"prefix":"10.1002","volume":"11","author":[{"given":"Yingxin","family":"Han","sequence":"first","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Centre for Systems Biomedicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5680-9579","authenticated-orcid":false,"given":"Liyan","family":"Ji","sequence":"additional","affiliation":[{"name":"GenePlus\u2010Beijing  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfang","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Technology School of Electronic and Information Engineering Xi'an Jiao Tong University  Xi'an China"},{"name":"GenePlus\u2010Beijing  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengya","family":"Ma","sequence":"additional","affiliation":[{"name":"GenePlus\u2010Beijing  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6278-5179","authenticated-orcid":false,"given":"Pansong","family":"Li","sequence":"additional","affiliation":[{"name":"GenePlus\u2010Beijing  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinge","family":"Xue","sequence":"additional","affiliation":[{"name":"Shanghai FLY Medical Laboratory  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai FLY Medical Laboratory  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqiu","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Centre for Systems Biomedicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Gong","sequence":"additional","affiliation":[{"name":"GenePlus\u2010Beijing  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jiang","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynecology Xinhua Hospital affiliated to Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xipeng","family":"Wang","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynecology Xinhua Hospital affiliated to Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Xie","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynecology Shenzhen People's Hospital  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boping","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynecology Shenzhen People's Hospital  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Technology School of Electronic and Information Engineering Xi'an Jiao Tong University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Genome Analysis Laboratory of the Ministry of Agriculture Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghua","family":"Han","sequence":"additional","affiliation":[{"name":"Genome Analysis Laboratory of the Ministry of Agriculture Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliang","family":"Deng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Centre for Systems Biomedicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yi","sequence":"additional","affiliation":[{"name":"GenePlus\u2010Beijing  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Gao","sequence":"additional","affiliation":[{"name":"Genome Analysis Laboratory of the Ministry of Agriculture Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences  Shenzhen China"},{"name":"Comparative Pediatrics and Nutrition Department of Veterinary and Animal Sciences Faculty of Health and Medical Sciences University of Copenhagen  Frederiksberg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Centre for Systems Biomedicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,19]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0434-2"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21338"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21492"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.06.008"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.008"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.316"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.67"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-019-0520-2"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/15592294.2018.1507197"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/21691401.2019.1634578"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017490"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2018.07.096"},{"key":"e_1_2_11_14_1","first-page":"101","article-title":"Genome\u2010wide DNA methylation analysis identifies candidate epigenetic markers and drivers of hepatocellular carcinoma","volume":"19","author":"Zheng Y","year":"2018","journal-title":"Brief Bioinform"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2019.00439"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20193349"},{"key":"e_1_2_11_17_1","first-page":"2138","article-title":"Integrated analysis of DNA methylation and transcriptome profiling of polycystic ovary syndrome","volume":"21","author":"Liu L","year":"2020","journal-title":"Mol Med Rep"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201101547"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.2064"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2012.1464"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1159\/000493016"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-3000"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12204"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2015.144"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13544"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2018-105745"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1313995110"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14248"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.05.026"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2015.150"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10478"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/gm323"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra072067"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003709"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.11.018"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-019-0719-9"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31539"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2016.07.006"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2017-108"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.13980"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1159\/000494005"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-45477-5"},{"key":"e_1_2_11_43_1","first-page":"2351","article-title":"Promoter hypermethylation of SOX11 promotes the progression of cervical cancer in vitro and in vivo","volume":"41","author":"Li X","year":"2019","journal-title":"Oncol Rep"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2018.06.014"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1177\/1010428317709126"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.30534"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-016-0263-9"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2015.08.001"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-016-0290-6"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6250"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3615"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-020-00886-6"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1009933108"},{"key":"e_1_2_11_54_1","first-page":"2431","article-title":"Upregulation and hypomethylation of lncRNA AFAP1AS1 predicts a poor prognosis and promotes the migration and invasion of cervical cancer","volume":"41","author":"Bo H","year":"2019","journal-title":"Oncol Rep"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-016-0472-2"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-018-0101-z"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1177\/1010428317697557"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12211"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201404976"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2016.1160187"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.12709"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.34172"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep02838"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1405801111"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1413363111"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-2668"},{"key":"e_1_2_11_67_1","first-page":"2777","article-title":"RSK4 inhibits breast cancer cell proliferation and invasion in vitro, and is correlated with estrogen receptor upregulation in breast cancer","volume":"42","author":"Huo H","year":"2019","journal-title":"Oncol Rep"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.463"},{"key":"e_1_2_11_69_1","first-page":"4301","article-title":"Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma","volume":"130","author":"Li M\u2010Y","year":"2020","journal-title":"J Clin Invest"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-018-0147-y"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aba9763"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01678-y"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004585"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.17082"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2014-15-2-r30"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.3390\/v9090248"},{"key":"e_1_2_11_77_1","doi-asserted-by":"publisher","DOI":"10.1309\/AJCPBRK7D1YIUWFP"},{"key":"e_1_2_11_78_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-10-232"},{"key":"e_1_2_11_79_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt459"},{"key":"e_1_2_11_80_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.196394.115"},{"key":"e_1_2_11_81_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3152"},{"key":"e_1_2_11_82_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.211854.116"},{"key":"e_1_2_11_83_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2012-13-7-r61"},{"key":"e_1_2_11_84_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-15-732"},{"key":"e_1_2_11_85_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016327"},{"key":"e_1_2_11_86_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_2_11_87_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12787"},{"key":"e_1_2_11_88_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx183"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.498","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ctm2.498","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.498","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T07:04:17Z","timestamp":1762931057000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7]]},"references-count":87,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["10.1002\/ctm2.498"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.498","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7]]},"article-number":"e498"}}