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Perkins, Ph.D. Distinguished Professorship in Biomedical Science Endowment","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Little is known about the role of the three Jumonji C (JmjC) enzymes in Plasmodium falciparum (Pf). Here, we show that JIB-04 and other established inhibitors of mammalian JmjC histone demethylases kill asexual blood stage parasites and are even more potent at blocking gametocyte development and gamete formation. In late stage parasites, JIB-04 increased levels of trimethylated lysine residues on histones, suggesting the inhibition of P.\u00a0falciparum Jumonji demethylase activity. These epigenetic defects coincide with deregulation of invasion, cell motor, and sexual development gene programs, including gene targets coregulated by the PfAP2-I transcription factor and chromatin-binding factor, PfBDP1. Mechanistically, we demonstrate that PfJmj3 converts 2-oxoglutarate to succinate in an iron-dependent manner consistent with mammalian Jumonji enzymes, and this catalytic activity is inhibited by JIB-04 and other Jumonji inhibitors. Our pharmacological studies of Jumonji activity in the malaria parasite provide evidence that inhibition of these enzymatic activities is detrimental to the parasite.<\/jats:p>","DOI":"10.1021\/acsinfecdis.9b00455","type":"journal-article","created":{"date-parts":[[2020,4,9]],"date-time":"2020-04-09T19:19:49Z","timestamp":1586459989000},"page":"1058-1075","source":"Crossref","is-referenced-by-count":36,"title":["Disruption of the\n                    <i>Plasmodium falciparum<\/i>\n                    Life Cycle through Transcriptional Reprogramming by Inhibitors of\nJumonji Demethylases"],"prefix":"10.1021","volume":"6","author":[{"given":"Krista A.","family":"Matthews","sequence":"first","affiliation":[{"name":"The University of Texas Southwestern Medical Center , , 6000 Harry Hines Blvd. , , ,","place":["Dallas, Texas, United States, 75390"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kossi M.","family":"Senagbe","sequence":"additional","affiliation":[{"name":"The University of Texas Southwestern Medical Center , , 6000 Harry Hines Blvd. , , ,","place":["Dallas, Texas, United States, 75390"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"No\u0308tzel","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine , , 1300 York Avenue, W-705 , , ,","place":["New York, New York, United States, 10065"]},{"name":"Weill Cornell Medicine , , 1300 York Avenue, W-705 , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Gonzales","sequence":"additional","affiliation":[{"name":"The University of Texas Southwestern Medical Center , , 6000 Harry Hines Blvd. , , ,","place":["Dallas, Texas, United States, 75390"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinran","family":"Tong","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine , , 1300 York Avenue, W-705 , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filipa","family":"Rijo-Ferreira","sequence":"additional","affiliation":[{"name":"The University of Texas Southwestern Medical Center , , 6000 Harry Hines Blvd. , , ,","place":["Dallas, Texas, United States, 75390"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natarajan V.","family":"Bhanu","sequence":"additional","affiliation":[{"name":"University of Pennsylvania , , 3400 Civic Center Blvd., Bldg. 421 , , ,","place":["Philadelphia, Pennsylvania, United States, 19104"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Miguel-Blanco","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline , , P.T.M. Severo Ochoa , , ,","place":["Tres Cantos, Madrid, Spain, 28760"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jose","family":"Lafuente-Monasterio","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline , , P.T.M. Severo Ochoa , , ,","place":["Tres Cantos, Madrid, Spain, 28760"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A.","family":"Garcia","sequence":"additional","affiliation":[{"name":"University of Pennsylvania , , 3400 Civic Center Blvd., Bldg. 421 , , ,","place":["Philadelphia, Pennsylvania, United States, 19104"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjo\u0308rn F. C.","family":"Kafsack","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine , , 1300 York Avenue, W-705 , , ,","place":["New York, New York, United States, 10065"]},{"name":"Weill Cornell Medicine , , 1300 York Avenue, W-705 , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1131-3689","authenticated-orcid":true,"given":"Elisabeth D.","family":"Martinez","sequence":"additional","affiliation":[{"name":"The University of Texas Southwestern Medical Center , , 6000 Harry Hines Blvd. , , ,","place":["Dallas, Texas, United States, 75390"]},{"name":"The University of Texas Southwestern Medical Center , , 6000 Harry Hines Blvd. , , ,","place":["Dallas, Texas, United States, 75390"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,4,9]]},"reference":[{"key":"2026090108011551200_cit1","volume-title":"World\nmalaria report 2018","author":"WHO.","year":"2018"},{"issue":"8","key":"2026090108011551200_cit2","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.1128\/EC.00093-10","article-title":"Epigenetics in Plasmodium: what do we really know?","volume":"9","author":"Merrick","year":"2010","journal-title":"Eukaryotic Cell"},{"issue":"5","key":"2026090108011551200_cit3","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1101\/gr.129692.111","article-title":"Transcriptional\nvariation in the malaria parasite Plasmodium falciparum","volume":"22","author":"Rovira-Graells","year":"2012","journal-title":"Genome Res."},{"issue":"9","key":"2026090108011551200_cit4","doi-asserted-by":"publisher","first-page":"e1000569","DOI":"10.1371\/journal.ppat.1000569","article-title":"Plasmodium falciparum heterochromatin protein 1 marks\ngenomic loci linked to phenotypic variation of exported virulence\nfactors","volume":"5","author":"Flueck","year":"2009","journal-title":"PLoS Pathog."},{"issue":"2","key":"2026090108011551200_cit5","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.chom.2008.12.012","article-title":"Genome-wide analysis of heterochromatin\nassociates clonally variant gene regulation with perinuclear repressive\ncenters in malaria parasites","volume":"5","author":"Lopez-Rubio","year":"2009","journal-title":"Cell Host Microbe"},{"issue":"2","key":"2026090108011551200_cit6","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.chom.2014.07.004","article-title":"Heterochromatin\nprotein 1 secures survival and transmission of malaria parasites","volume":"16","author":"Brancucci","year":"2014","journal-title":"Cell Host Microbe"},{"key":"2026090108011551200_cit7","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1146\/annurev-micro-090816-093841","article-title":"Variant Gene\nExpression and Antigenic Variation by\nMalaria Parasites","volume":"71","author":"Deitsch","year":"2017","journal-title":"Annu. 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Pharmacol."},{"key":"2026090108011551200_cit23","doi-asserted-by":"publisher","first-page":"2035","DOI":"10.1038\/ncomms3035","article-title":"A small molecule modulates Jumonji histone demethylase\nactivity and selectively inhibits cancer growth","volume":"4","author":"Wang","year":"2013","journal-title":"Nat. Commun."},{"issue":"16","key":"2026090108011551200_cit24","doi-asserted-by":"publisher","first-page":"2243","DOI":"10.4155\/fmc.15.140","article-title":"Successful\nstrategies in the discovery\nof small-molecule epigenetic modulators with anticancer potential","volume":"7","author":"Bayo","year":"2015","journal-title":"Future Med. Chem."},{"issue":"13","key":"2026090108011551200_cit25","doi-asserted-by":"publisher","first-page":"2174","DOI":"10.1039\/C6CC09882G","article-title":"The small\nmolecule JIB-04 disrupts O2 binding in the Fe-dependent histone demethylase\nKDM4A\/JMJD2A","volume":"53","author":"Cascella","year":"2017","journal-title":"Chem. Commun. (Cambridge, U. 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