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

Item Type:	Article
Title:	UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs
Creators Name:	Gozdecka, M. and Meduri, E. and Mazan, M. and Tzelepis, K. and Dudek, M. and Knights, A.J. and Pardo, M. and Yu, L. and Choudhary, J.S. and Metzakopian, E. and Iyer, V. and Yun, H. and Park, N. and Varela, I. and Bautista, R. and Collord, G. and Dovey, O. and Garyfallos, D.A. and De Braekeleer, E. and Kondo, S. and Cooper, J. and Göttgens, B. and Bullinger, L. and Northcott, P.A. and Adams, D. and Vassiliou, G.S. and Huntly, B.J.P.
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.
Keywords:	Acute Myeloid Leukaemia, Cancer Stem Cells, Epigenetics, Animals, Mice
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	50
Number:	6
Page Range:	883-894
Date:	June 2018
Official Publication:	https://doi.org/10.1038/s41588-018-0114-z
PubMed:	View item in PubMed

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