dc.contributor.author | Gozdecka, M | |
dc.contributor.author | Meduri, E | |
dc.contributor.author | Mazan, M | |
dc.contributor.author | Tzelepis, K | |
dc.contributor.author | Dudek, M | |
dc.contributor.author | Knights, AJ | |
dc.contributor.author | Pardo, M | |
dc.contributor.author | Yu, L | |
dc.contributor.author | Choudhary, JS | |
dc.contributor.author | Metzakopian, E | |
dc.contributor.author | Iyer, V | |
dc.contributor.author | Yun, H | |
dc.contributor.author | Park, N | |
dc.contributor.author | Varela, I | |
dc.contributor.author | Bautista, R | |
dc.contributor.author | Collord, G | |
dc.contributor.author | Dovey, O | |
dc.contributor.author | Garyfallos, DA | |
dc.contributor.author | De Braekeleer, E | |
dc.contributor.author | Kondo, S | |
dc.contributor.author | Cooper, J | |
dc.contributor.author | Göttgens, B | |
dc.contributor.author | Bullinger, L | |
dc.contributor.author | Northcott, PA | |
dc.contributor.author | Adams, D | |
dc.contributor.author | Vassiliou, GS | |
dc.contributor.author | Huntly, BJP | |
dc.date.accessioned | 2020-10-16T09:52:01Z | |
dc.date.issued | 2018-06-01 | |
dc.identifier.citation | Nature genetics, 2018, 50 (6), pp. 883 - 894 | |
dc.identifier.issn | 1061-4036 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4176 | |
dc.identifier.eissn | 1546-1718 | |
dc.identifier.doi | 10.1038/s41588-018-0114-z | |
dc.description.abstract | The 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 883 - 894 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Cell Line | |
dc.subject | Chromatin | |
dc.subject | Animals | |
dc.subject | Mice, Inbred C57BL | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Leukemia, Myeloid | |
dc.subject | Histones | |
dc.subject | Proteomics | |
dc.subject | Chromatin Assembly and Disassembly | |
dc.subject | Gene Expression Regulation, Leukemic | |
dc.subject | Regulatory Sequences, Nucleic Acid | |
dc.subject | Proto-Oncogene Proteins c-ets | |
dc.subject | GATA Transcription Factors | |
dc.subject | Enhancer Elements, Genetic | |
dc.subject | Transcriptional Activation | |
dc.subject | Histone Demethylases | |
dc.subject | HEK293 Cells | |
dc.title | UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-03-19 | |
rioxxterms.versionofrecord | 10.1038/s41588-018-0114-z | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2018-06 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature genetics | |
pubs.issue | 6 | |
pubs.notes | Not known | |
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.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-status | Published | |
pubs.volume | 50 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Functional Proteomics Group | |
dc.contributor.icrauthor | Pardo Calvo, Maria Mercedes | |
dc.contributor.icrauthor | Choudhary, Jyoti | |