{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:52:25Z","timestamp":1786978345181,"version":"build-2736575974"},"reference-count":73,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T00:00:00Z","timestamp":1655078400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["ACIF\/2019\/139"],"award-info":[{"award-number":["ACIF\/2019\/139"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["APOSTD\/2020\/123"],"award-info":[{"award-number":["APOSTD\/2020\/123"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["PROMETEO\/2018\/137"],"award-info":[{"award-number":["PROMETEO\/2018\/137"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CP20\/00120"],"award-info":[{"award-number":["CP20\/00120"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["FI19\/00110"],"award-info":[{"award-number":["FI19\/00110"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI18\/00323"],"award-info":[{"award-number":["PI18\/00323"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Uterine leiomyomas (ULs) are the most common benign tumors in women of reproductive age. Despite the high prevalence, tumor pathology remains unclear, which hampers the development of safe and effective treatments. Epigenetic mechanisms appear to be involved in UL development, particularly via DNA methylation that regulates gene expression. We aimed to determine the relationship between DNA methylation and gene expression in UL compared with adjacent myometrium (MM) to identify molecular mechanisms involved in UL formation that are under epigenetic control. Our results showed a different DNA methylation profile between UL and MM, leading to hypermethylation of UL, and a different global transcriptome profile. Integration of DNA methylation and whole\u2010transcriptome RNA\u2010sequencing data identified 93 genes regulated by methylation, with 22 hypomethylated\/upregulated and 71 hypermethylated\/downregulated. Functional enrichment analysis showed dysregulated biological processes and molecular functions involved in metabolism and cell physiology, response to extracellular signals, invasion, and proliferation, as well as pathways related to uterine biology and cancer. Cellular components such as cell membranes, vesicles, extracellular matrix, and cell junctions were dysregulated in UL. In addition, we found hypomethylation\/upregulation of oncogenes (\n                    <jats:italic>PRL<\/jats:italic>\n                    ,\n                    <jats:italic>ATP8B4<\/jats:italic>\n                    ,\n                    <jats:italic>CEMIP<\/jats:italic>\n                    ,\n                    <jats:italic>ZPMS2\u2010AS1<\/jats:italic>\n                    ,\n                    <jats:italic>RIMS2<\/jats:italic>\n                    ,\n                    <jats:italic>TFAP2C<\/jats:italic>\n                    ) and hypermethylation\/downregulation of tumor suppressor genes (\n                    <jats:italic>EFEMP1<\/jats:italic>\n                    ,\n                    <jats:italic>FBLN2<\/jats:italic>\n                    ,\n                    <jats:italic>ARHGAP10<\/jats:italic>\n                    ,\n                    <jats:italic>HTATIP2<\/jats:italic>\n                    ), which are related to proliferation, invasion, altered metabolism, deposition of extracellular matrix, and Wnt\/\u03b2\u2010catenin pathway dysregulation. This confirms that key processes of UL development are under DNA methylation control. Finally, inhibition of DNA methyltransferases by 5\u2010aza\u20102'\u2010deoxycitidine increased the expression of hypermethylated\/downregulated genes in UL cells\n                    <jats:italic>in vitro<\/jats:italic>\n                    . In conclusion, gene regulation by DNA methylation is implicated in UL pathogenesis, and reversion of this methylation could offer a therapeutic option for UL. \u00a9 2022 The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.5920","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T14:58:33Z","timestamp":1650985113000},"page":"663-673","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Integrative analysis of the DNA methylome and transcriptome in uterine leiomyoma shows altered regulation of genes involved in metabolism, proliferation, extracellular matrix, and vesicles"],"prefix":"10.1002","volume":"257","author":[{"given":"Mar\u00eda Cristina","family":"Carbajo\u2010Garc\u00eda","sequence":"first","affiliation":[{"name":"Fundaci\u00f3n IVI Instituto de Investigaci\u00f3n Sanitaria La Fe  Valencia Spain"},{"name":"Departamento de Pediatr\u00eda, Obstetricia y Ginecolog\u00eda Universidad de Valencia  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Corach\u00e1n","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n IVI Instituto de Investigaci\u00f3n Sanitaria La Fe  Valencia Spain"},{"name":"Departamento de Pediatr\u00eda, Obstetricia y Ginecolog\u00eda Universidad de Valencia  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Ju\u00e1rez\u2010Barber","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n IVI Instituto de Investigaci\u00f3n Sanitaria La Fe  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Monle\u00f3n","sequence":"additional","affiliation":[{"name":"Hospital Universitario y Polit\u00e9cnico La Fe  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Pay\u00e1","sequence":"additional","affiliation":[{"name":"Hospital Universitario y Polit\u00e9cnico La Fe  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Trelis","sequence":"additional","affiliation":[{"name":"Hospital Universitario y Polit\u00e9cnico La Fe  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Qui\u00f1onero","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n IVI Instituto de Investigaci\u00f3n Sanitaria La Fe  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Pellicer","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n IVI Instituto de Investigaci\u00f3n Sanitaria La Fe  Valencia Spain"},{"name":"IVIRMA Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4302-7871","authenticated-orcid":false,"given":"Hortensia","family":"Ferrero","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n IVI Instituto de Investigaci\u00f3n Sanitaria La Fe  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0b013e31828acca0"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1209993"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)03622-9"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmw023"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.5468\/ogs.2018.61.2.192"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2018.04.040"},{"key":"e_1_2_8_8_1","first-page":"CD007687","article-title":"Mifepristone for uterine fibroids","volume":"2012","author":"Tristan M","year":"2012","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.43"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-021-00618-y"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1518752113"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.14640"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.4161\/epi.27473"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/1933719115584449"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19041166"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-91037-1"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaa309"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13061391"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gap010"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033284"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0066632"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.4161\/epi.6.6.16196"},{"key":"e_1_2_8_23_1","first-page":"389","article-title":"Validation of a DNA methylation microarray for 850,000 CpG sites of the human genome enriched in enhancer sequences","volume":"8","author":"Moran S","year":"2016","journal-title":"Epigenetics"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu049"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"e_1_2_8_27_1","unstructured":"R Core TeamR: A language and environment for statistical computing. R Foundation for Statistical Computing Vienna Austria. 2020. [Accessed 23 December 2020].https:\/\/www.R-project.org\/."},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.14806\/ej.17.1.200"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts611"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz931"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12958-021-00790-5"},{"key":"e_1_2_8_33_1","unstructured":"WarnesGR BolkerB BonebakkerL et al.gplots: Various R Programming Tools for Plotting Data. R package version 3.1.1.2020.https:\/\/CRAN.R-project.org\/package=gplots."},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-24277-4"},{"key":"e_1_2_8_35_1","unstructured":"NeuwirthE.RColorBrewer: ColorBrewer Palettes. R package version 1.1\u20102. 2014.https:\/\/CRAN.R-roject.org\/package=RColorBrewer."},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deh698"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.2174\/1871520619666190409102855"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00404-017-4515-5"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpobgyn.2015.11.018"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-3278"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.11.077"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqaa143"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.12.039"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20246151"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2014.00053"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1313650110"},{"key":"e_1_2_8_48_1","first-page":"100","article-title":"Uterine fibroids: diagnosis and treatment","volume":"95","author":"De La Cruz MS","year":"2017","journal-title":"Am Fam Physician"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2004.04.030"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmx032"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2018.02.013"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2015.02.010"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2019.04.004"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1209318109"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2012.01.002"},{"key":"e_1_2_8_56_1","first-page":"689","article-title":"Genes regulated by interferon\u2010gamma in human uterine microvascular endothelial cells","volume":"20","author":"Kitaya K","year":"2007","journal-title":"Int J Mol Med"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-018-0683-9"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1043-2760(02)00603-3"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep30652"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111507"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0387-9"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-020-1157-7"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8263"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-021-04174-6"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2018.4276"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.401"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0168408"},{"key":"e_1_2_8_68_1","first-page":"4145","article-title":"Aberrant methylation of HTATIP2 and UCHL1 as a predictive biomarker for cholangiocarcinoma","volume":"17","author":"Nanok C","year":"2018","journal-title":"Mol Med Rep"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-0409"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-009-0992-0"},{"key":"e_1_2_8_71_1","first-page":"4629","article-title":"KCNMA1\u2010AS1 attenuates apoptosis of epithelial ovarian cancer cells and serves as a risk factor for poor prognosis of epithelial ovarian cancer","volume":"23","author":"Ma SY","year":"2019","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.2217\/fon-2020-0618"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15780"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20180820"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5920","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.5920","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5920","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T09:48:01Z","timestamp":1761040081000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.5920"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,13]]},"references-count":73,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["10.1002\/path.5920"],"URL":"https:\/\/doi.org\/10.1002\/path.5920","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,13]]},"assertion":[{"value":"2022-01-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}