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UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.

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Date
2018-06
ICR Author
Pardo Calvo, Maria Mercedes
Choudhary, Jyoti
Author
Gozdecka, M
Meduri, E
Mazan, M
Tzelepis, K
Dudek, M
Knights, AJ
Pardo, M
Yu, L
Choudhary, JS
Metzakopian, E
Iyer, V
Yun, H
Park, N
Varela, I
Bautista, R
Collord, G
Dovey, O
Garyfallos, DA
De Braekeleer, E
Kondo, S
Cooper, J
Göttgens, B
Bullinger, L
Northcott, PA
Adams, D
Vassiliou, GS
Huntly, BJP
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Type
Journal Article
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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.
URI
https://repository.icr.ac.uk/handle/internal/4176
DOI
https://doi.org/10.1038/s41588-018-0114-z
Collections
  • Cancer Biology
Subject
Cell Line
Chromatin
Animals
Mice, Inbred C57BL
Humans
Mice
Leukemia, Myeloid
Histones
Proteomics
Chromatin Assembly and Disassembly
Gene Expression Regulation, Leukemic
Regulatory Sequences, Nucleic Acid
Proto-Oncogene Proteins c-ets
GATA Transcription Factors
Enhancer Elements, Genetic
Transcriptional Activation
Histone Demethylases
HEK293 Cells
Research team
Functional Proteomics Group
Language
eng
Date accepted
2018-03-19
License start date
2018-06
Citation
Nature genetics, 2018, 50 (6), pp. 883 - 894

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