{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:38:26Z","timestamp":1791837506821,"version":"4.3.4"},"reference-count":43,"publisher":"The Endocrine Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>The von Hippel Lindau (VHL) protein is a key executor of the cellular hypoxic response that is compromised in preeclampsia, a serious disorder complicating 5% to 7% of pregnancies. To date, the mechanisms controlling VHL gene expression in the human placenta remain elusive.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>We examined VHL epigenetic regulation in normal pregnancy and in preeclampsia, a pathology characterized by placental hypoxia.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design, Setting, and Participants<\/jats:title>\n                  <jats:p>Placentae were obtained from early-onset preeclampsia (n = 56; &amp;lt;34 weeks of gestation) and late-onset preeclampsia (n = 19; \u226534 weeks of gestation). Placentae from healthy normotensive age-matched preterm control (n = 43) and term control (n = 23) pregnancies were included as controls.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Main Outcome Measure(s)<\/jats:title>\n                  <jats:p>We measured the activity of Jumonji domain containing protein 6 (JMJD6), a ferrous iron (Fe2+)\u2013 and oxygen-dependent histone demethylase, and examined its function in the epigenetic control of VHL.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>JMJD6 regulates VHL gene expression in the human placenta. VHL downregulation in preeclampsia is dependent on decreased JMJD6 demethylase activity due to hypoxia and reduced Fe2+ bioavailability. Chromatin immunoprecipitation assays revealed decreased association of JMJD6 and its histone targets with the VHL promoter. Findings in preeclampsia were corroborated in a murine model of pharmacological hypoxia using FG-4592. Placentae from FG-4592\u2013treated mice exhibited reduced VHL levels, accompanied by placental morphological alterations and reduced pup weights. Notably, Fe2+ supplementation rescued JMJD6 histone demethylase activity in histone from E-PE and FG-4592\u2013treated mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our study uncovers epigenetic regulation of VHL and its functional consequences for altered oxygen and iron homeostasis in preeclampsia.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/jc.2017-02197","type":"journal-article","created":{"date-parts":[[2018,1,24]],"date-time":"2018-01-24T19:01:34Z","timestamp":1516820494000},"page":"1545-1557","source":"Crossref","is-referenced-by-count":31,"title":["Compromised JMJD6 Histone Demethylase Activity Affects VHL Gene Repression in Preeclampsia"],"prefix":"10.1210","volume":"103","author":[{"given":"Sruthi","family":"Alahari","sequence":"first","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada"},{"name":"Department of Physiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Post","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Toronto, Toronto, Ontario, Canada"},{"name":"Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Rolfo","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Weksberg","sequence":"additional","affiliation":[{"name":"Genetics & Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Caniggia","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada"},{"name":"Department of Physiology, University of Toronto, Toronto, Ontario, Canada"},{"name":"Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2018,1,24]]},"reference":[{"issue":"6733","key":"2020071622172209900_B1","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/20459","article-title":"The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis","volume":"399","author":"Maxwell","year":"1999","journal-title":"Nature"},{"issue":"5112","key":"2020071622172209900_B2","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1126\/science.8493574","article-title":"Identification of the von Hippel-Lindau disease tumor suppressor gene","volume":"260","author":"Latif","year":"1993","journal-title":"Science"},{"issue":"17","key":"2020071622172209900_B3","doi-asserted-by":"crossref","first-page":"9102","DOI":"10.1073\/pnas.94.17.9102","article-title":"Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice","volume":"94","author":"Gnarra","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"2020071622172209900_B4","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1095\/biolreprod.106.051557","article-title":"Dynamic HIF1A regulation during human placental development","volume":"75","author":"Ietta","year":"2006","journal-title":"Biol Reprod"},{"issue":"1","key":"2020071622172209900_B5","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/ng0594-85","article-title":"Mutations of the VHL tumour suppressor gene in renal carcinoma","volume":"7","author":"Gnarra","year":"1994","journal-title":"Nat Genet"},{"issue":"8","key":"2020071622172209900_B6","doi-asserted-by":"crossref","first-page":"3012","DOI":"10.1210\/en.2015-1262","article-title":"Jumonji domain containing protein 6: a novel oxygen sensor in the human placenta","volume":"156","author":"Alahari","year":"2015","journal-title":"Endocrinology"},{"issue":"1","key":"2020071622172209900_B7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0968-0004(00)01700-X","article-title":"JmjC: cupin metalloenzyme-like domains in jumonji, hairless and phospholipase A2beta","volume":"26","author":"Clissold","year":"2001","journal-title":"Trends Biochem Sci"},{"issue":"7078","key":"2020071622172209900_B8","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/nature04433","article-title":"Histone demethylation by a family of JmjC domain-containing proteins","volume":"439","author":"Tsukada","year":"2005","journal-title":"Nature"},{"issue":"5849","key":"2020071622172209900_B9","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1126\/science.1145801","article-title":"JMJD6 is a histone arginine demethylase","volume":"318","author":"Chang","year":"2007","journal-title":"Science"},{"issue":"10","key":"2020071622172209900_B10","doi-asserted-by":"crossref","first-page":"e13769","DOI":"10.1371\/journal.pone.0013769","article-title":"Analysis of Jmjd6 cellular localization and testing for its involvement in histone demethylation","volume":"5","author":"Hahn","year":"2010","journal-title":"PLoS One"},{"issue":"1","key":"2020071622172209900_B11","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s13148-016-0205-6","article-title":"The epigenetic modifier JMJD6 is amplified in mammary tumors and cooperates with c-Myc to enhance cellular transformation, tumor progression, and metastasis","volume":"8","author":"Aprelikova","year":"2016","journal-title":"Clin Epigenetics"},{"issue":"11","key":"2020071622172209900_B12","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1080\/15384101.2015.1033595","article-title":"PRMT5-mediated symmetric arginine dimethylation is attenuated by mutant huntingtin and is impaired in Huntington\u2019s disease (HD)","volume":"14","author":"Ratovitski","year":"2015","journal-title":"Cell Cycle"},{"issue":"5","key":"2020071622172209900_B13","first-page":"1122","article-title":"Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists\u2019 Task Force on Hypertension in Pregnancy","volume":"122","author":"American College of Obstetricians and Gynecologists","year":"2013","journal-title":"Obstet Gynecol"},{"issue":"9237","key":"2020071622172209900_B14","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1016\/S0140-6736(00)02800-2","article-title":"Pre-eclampsia","volume":"356","author":"Walker","year":"2000","journal-title":"Lancet"},{"issue":"2","key":"2020071622172209900_B15","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1067\/mob.2002.123895","article-title":"Abnormal iron parameters in the pregnancy syndrome preeclampsia","volume":"187","author":"Rayman","year":"2002","journal-title":"Am J Obstet Gynecol"},{"issue":"7","key":"2020071622172209900_B16","doi-asserted-by":"crossref","first-page":"4299","DOI":"10.1210\/jc.2005-0078","article-title":"Molecular evidence of placental hypoxia in preeclampsia","volume":"90","author":"Soleymanlou","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"2020071622172209900_B17","doi-asserted-by":"crossref","first-page":"e13288","DOI":"10.1371\/journal.pone.0013288","article-title":"Abnormalities in oxygen sensing define early and late onset preeclampsia as distinct pathologies","volume":"5","author":"Rolfo","year":"2010","journal-title":"PLoS One"},{"issue":"3","key":"2020071622172209900_B18","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1210\/en.2012-1823","article-title":"Where polarity meets fusion: role of Par6 in trophoblast differentiation during placental development and preeclampsia","volume":"154","author":"Sivasubramaniyam","year":"2013","journal-title":"Endocrinology"},{"issue":"13","key":"2020071622172209900_B19","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1128\/MCB.01341-10","article-title":"The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3","volume":"31","author":"Rahman","year":"2011","journal-title":"Mol Cell Biol"},{"issue":"4","key":"2020071622172209900_B20","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(\u2212Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"issue":"4","key":"2020071622172209900_B21","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1681\/ASN.2015030241","article-title":"Roxadustat (FG-4592): correction of anemia in incident dialysis patients","volume":"27","author":"Besarab","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"2020071622172209900_B22","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.brainres.2015.12.017","article-title":"Stabilization of HIF-1\u03b1 by FG-4592 promotes functional recovery and neural protection in experimental spinal cord injury","volume":"1632","author":"Wu","year":"2016","journal-title":"Brain Res"},{"issue":"3","key":"2020071622172209900_B23","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1042\/BJ20140754","article-title":"Chromatin and oxygen sensing in the context of JmjC histone demethylases","volume":"462","author":"Shmakova","year":"2014","journal-title":"Biochem J"},{"issue":"7","key":"2020071622172209900_B24","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1016\/j.cell.2013.10.056","article-title":"Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release","volume":"155","author":"Liu","year":"2013","journal-title":"Cell"},{"key":"2020071622172209900_B25","doi-asserted-by":"crossref","first-page":"11974","DOI":"10.1038\/ncomms11974","article-title":"Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases","volume":"7","author":"Walport","year":"2016","journal-title":"Nat Commun"},{"key":"2020071622172209900_B26","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.3109\/14767058.2013.776533","article-title":"Comparison of clinical and laboratory findings in early- and late-onset preeclampsia","volume":"26","author":"Kucukgoz Gulec","year":"2013","journal-title":"J Matern Fetal Neonatal Med"},{"issue":"1","key":"2020071622172209900_B27","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s00404-014-3176-x","article-title":"Comparison of clinical and perinatal outcomes in early- and late-onset preeclampsia","volume":"290","author":"Madazli","year":"2014","journal-title":"Arch Gynecol Obstet"},{"issue":"8","key":"2020071622172209900_B28","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1097\/OGX.0b013e3182331028","article-title":"A critical review of early-onset and late-onset preeclampsia","volume":"66","author":"Raymond","year":"2011","journal-title":"Obstet Gynecol Surv"},{"key":"2020071622172209900_B29","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1042\/CS20030385","article-title":"Second trimester Doppler ultrasound screening of the uterine arteries differentiates between subsequent normal and poor outcomes of hypertensive pregnancy: two different pathophysiological entities","volume":"106","author":"Aardema","year":"2004","journal-title":"Clin Sci"},{"key":"2020071622172209900_B30","doi-asserted-by":"crossref","first-page":"491","DOI":"10.3109\/14767058.2012.733766","article-title":"The severity of hypoxic changes and oxidative DNA damage in the placenta of early-onset preeclamptic women and fetal growth restriction","volume":"26","author":"Kimura","year":"2012","journal-title":"J Matern Fetal Neonatal Med"},{"issue":"4-5","key":"2020071622172209900_B31","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.placenta.2005.04.002","article-title":"Expression of von Hippel Lindau (pVHL) protein in placentae from normal pregnant women and women with preeclampsia","volume":"27","author":"Rajakumar","year":"2006","journal-title":"Placenta"},{"issue":"21","key":"2020071622172209900_B32","doi-asserted-by":"crossref","first-page":"9700","DOI":"10.1073\/pnas.91.21.9700","article-title":"Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma","volume":"91","author":"Herman","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"issue":"4","key":"2020071622172209900_B33","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1158\/0008-5472.CAN-05-3074","article-title":"Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer","volume":"66","author":"Banks","year":"2006","journal-title":"Cancer Res"},{"issue":"5","key":"2020071622172209900_B34","doi-asserted-by":"crossref","first-page":"e62969","DOI":"10.1371\/journal.pone.0062969","article-title":"Early onset pre-eclampsia is associated with altered DNA methylation of cortisol-signalling and steroidogenic genes in the placenta","volume":"8","author":"Hogg","year":"2013","journal-title":"PLoS One"},{"issue":"10","key":"2020071622172209900_B35","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1093\/molehr\/gat044","article-title":"Widespread DNA hypomethylation at gene enhancer regions in placentas associated with early-onset pre-eclampsia","volume":"19","author":"Blair","year":"2013","journal-title":"Mol Hum Reprod"},{"issue":"9","key":"2020071622172209900_B36","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1038\/ejhg.2010.63","article-title":"DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia","volume":"18","author":"Yuen","year":"2010","journal-title":"Eur J Hum Genet"},{"issue":"1","key":"2020071622172209900_B37","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/1471-2164-10-143","article-title":"Determination of enriched histone modifications in non-genic portions of the human genome","volume":"10","author":"Rosenfeld","year":"2009","journal-title":"BMC Genomics"},{"issue":"8","key":"2020071622172209900_B38","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1111\/j.1440-1681.2011.05661.x","article-title":"Essential but toxic: controlling the flux of iron in the body","volume":"39","author":"Anderson","year":"2012","journal-title":"Clin Exp Pharmacol Physiol"},{"issue":"4","key":"2020071622172209900_B39","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.thromres.2009.05.016","article-title":"Role of the syncytium in placenta-mediated complications of preeclampsia","volume":"124","author":"Guller","year":"2009","journal-title":"Thromb Res"},{"issue":"28","key":"2020071622172209900_B40","doi-asserted-by":"crossref","first-page":"21048","DOI":"10.1074\/jbc.M000636200","article-title":"Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency","volume":"275","author":"Mukhopadhyay","year":"2000","journal-title":"J Biol Chem"},{"issue":"1","key":"2020071622172209900_B41","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0301-2115(98)00261-9","article-title":"Defective antioxidant mechanisms via changes in serum ceruloplasmin and total iron binding capacity of serum in women with pre-eclampsia","volume":"84","author":"Vitoratos","year":"1999","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"issue":"10","key":"2020071622172209900_B42","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1038\/labinvest.2008.74","article-title":"Placental expression of ceruloplasmin in pregnancies complicated by severe preeclampsia","volume":"88","author":"Guller","year":"2008","journal-title":"Lab Invest"},{"issue":"13","key":"2020071622172209900_B43","doi-asserted-by":"crossref","first-page":"621","DOI":"10.3923\/pjbs.2010.621.627","article-title":"Serum level and antioxidant activity of ceruloplasmin in preeclampsia","volume":"13","author":"Shakour-Shahabi","year":"2010","journal-title":"Pak J Biol Sci"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/103\/4\/1545\/24565673\/jc.2017-02197.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/103\/4\/1545\/24565673\/jc.2017-02197.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T10:37:13Z","timestamp":1594982233000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/103\/4\/1545\/4822912"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,24]]},"references-count":43,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2018,4,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2017-02197","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,4]]},"published":{"date-parts":[[2018,1,24]]}}}