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, A.J.; Pardo, M.; Yu, L.; Choudhary, J.S.; Metzakopian, E.; Iyer, V.; Yun, H.; Park, N.; Varela, I.; Bautista, R.; Collord, G.; Dovey, O.; Garyfallos, D.A.; De Braekeleer, E.; Kondo, S.; Cooper, J.; Göttgens, B.; Bullinger, L.; Northcott, P.A.; Adams, D.; Vassiliou, G.S.; Huntly, B.J.P.

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

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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., Meduri, E., Mazan, M., Tzelepis, K., Dudek, M., Knights, A.J., Pardo, M., Yu, L., Choudhary, J.S., Metzakopian, E., Iyer, V., Yun, H., Park, N., Varela, I., Bautista, R., Collord, G., Dovey, O., Garyfallos, D.A., De Braekeleer, E., Kondo, S., Cooper, J., Göttgens, B., Bullinger, L., Northcott, P.A., Adams, D., 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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