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

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, Gottgens B, Bullinger L, Northcott PA, Adams D, Vassiliou GS, Huntly BJP (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Nature Genetics Nature Publishing Group

Book Volume: 50

Pages Range: 883-894

Journal Issue: 6

DOI: 10.1038/s41588-018-0114-z

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.

Additional Organisation(s)

Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

Wellcome Trust Sanger Institute - Genome Research Limited GB United Kingdom (GB) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) University of Cambridge GB United Kingdom (GB) Universidad de Cantabria (UC) ES Spain (ES) University of Tokyo JP Japan (JP) Universität Ulm DE Germany (DE)

How to cite

APA:

Gozdecka, M., Meduri, E., Mazan, M., Tzelepis, K., Dudek, M., Knights, A.J.,... Huntly, B.J.P. (2018). UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. Nature Genetics, 50(6), 883-894. https://doi.org/10.1038/s41588-018-0114-z

MLA:

Gozdecka, Malgorzata, et al. "UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs." Nature Genetics 50.6 (2018): 883-894.

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