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dc.contributor.authorGozdecka, Men_US
dc.contributor.authorMeduri, Een_US
dc.contributor.authorMazan, Men_US
dc.contributor.authorTzelepis, Ken_US
dc.contributor.authorDudek, Men_US
dc.contributor.authorKnights, AJen_US
dc.contributor.authorPardo, Men_US
dc.contributor.authorYu, Len_US
dc.contributor.authorChoudhary, JSen_US
dc.contributor.authorMetzakopian, Een_US
dc.contributor.authorIyer, Ven_US
dc.contributor.authorYun, Hen_US
dc.contributor.authorPark, Nen_US
dc.contributor.authorVarela, Ien_US
dc.contributor.authorBautista, Ren_US
dc.contributor.authorCollord, Gen_US
dc.contributor.authorDovey, Oen_US
dc.contributor.authorGaryfallos, DAen_US
dc.contributor.authorDe Braekeleer, Een_US
dc.contributor.authorKondo, Sen_US
dc.contributor.authorCooper, Jen_US
dc.contributor.authorGöttgens, Ben_US
dc.contributor.authorBullinger, Len_US
dc.contributor.authorNorthcott, PAen_US
dc.contributor.authorAdams, Den_US
dc.contributor.authorVassiliou, GSen_US
dc.contributor.authorHuntly, BJPen_US
dc.date.accessioned2020-10-16T09:52:01Z
dc.date.issued2018-06en_US
dc.identifier.citationNature genetics, 2018, 50 (6), pp. 883 - 894en_US
dc.identifier.issn1546-1718en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4176
dc.identifier.eissn1546-1718en_US
dc.identifier.doi10.1038/s41588-018-0114-zen_US
dc.description.abstractThe histone H3 Lys27-specific demethylase UTX (or KDM6A) is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (or KDM6C). In keeping with this, we demonstrate concomitant loss/mutation of KDM6A (UTX) and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27me3 but significant and bidirectional alterations in H3K27ac and chromatin accessibility; a predominant loss of H3K4me1 modifications; alterations in ETS and GATA-factor binding; and altered gene expression after Utx loss. By integrating proteomic and genomic analyses, we link these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex and enhanced pioneering activity of ETS factors during evolution to AML. Collectively, our findings identify a dual role for UTX in suppressing acute myeloid leukemia via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs.en_US
dc.formatPrint-Electronicen_US
dc.format.extent883 - 894en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_US
dc.subjectCell Lineen_US
dc.subjectChromatinen_US
dc.subjectAnimalsen_US
dc.subjectMice, Inbred C57BLen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectLeukemia, Myeloiden_US
dc.subjectHistonesen_US
dc.subjectProteomicsen_US
dc.subjectChromatin Assembly and Disassemblyen_US
dc.subjectGene Expression Regulation, Leukemicen_US
dc.subjectRegulatory Sequences, Nucleic Aciden_US
dc.subjectProto-Oncogene Proteins c-etsen_US
dc.subjectGATA Transcription Factorsen_US
dc.subjectEnhancer Elements, Geneticen_US
dc.subjectTranscriptional Activationen_US
dc.subjectHistone Demethylasesen_US
dc.subjectHEK293 Cellsen_US
dc.titleUTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-03-19en_US
rioxxterms.versionofrecord10.1038/s41588-018-0114-zen_US
rioxxterms.licenseref.startdate2018-06en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfNature geneticsen_US
pubs.issue6en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Functional Proteomics Group
pubs.publication-statusPublisheden_US
pubs.volume50en_US
pubs.embargo.termsNot knownen_US
icr.researchteamFunctional Proteomics Groupen_US
dc.contributor.icrauthorPardo Calvo, Maria Mercedesen_US
dc.contributor.icrauthorChoudhary, Jyotien_US


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