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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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Huntly, BJP 
Meduri, Eshwar 
Yun, Haiyang 
Gottgens, Bertie 


The H3K27 lysine-specific demethylase UTX is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukemogenesis through non-catalytic functions, a property shared with its catalytically inactive Y-chromosome paralogue, UTY. In keeping with this, we demonstrate concomitant loss/mutation of UTX and UTY in multiple human cancers. Mechanistically, global genomic profiling revealed only minor changes in H3K27Me3, but significant and bidirectional alterations of H3K27Ac and chromatin accessibility, a predominant loss of H3K4Me1 modifications, alterations in ETS and GATA factor binding and altered gene expression upon 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 reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs



Animals, Cell Line, Chromatin, Chromatin Assembly and Disassembly, Enhancer Elements, Genetic, GATA Transcription Factors, Gene Expression Regulation, Leukemic, HEK293 Cells, Histone Demethylases, Histones, Humans, Leukemia, Myeloid, Mice, Mice, Inbred C57BL, Proteomics, Proto-Oncogene Proteins c-ets, Regulatory Sequences, Nucleic Acid, Transcriptional Activation

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Nature Genetics

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Nature Publishing Group
Leukaemia & Lymphoma Research (12029)
Cancer Research UK (21762)
Wellcome Trust (206328/Z/17/Z)
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/M010392/1)
Medical Research Council (MR/R009708/1)
Wellcome Trust (097922/Z/11/Z)
Wellcome Trust (100140/Z/12/Z)
European Research Council (647685)
Cancer Research UK (23015)
This study was primarily funded by a joint Bloodwise Program Grant (17006) to B.H. and G.S.V. Work in the Huntly lab is also funded by an ERC consolidator award (grant 647685 COMAL), a CRUK program award, the Medical Research Council, (MRC) the Welcome Trust (WT) and the Cambridge NIHR BRC. We acknowledge the WT/MRC center grant (097922/Z/11/Z) and support from WT strategic award 100140. G.S.V. is funded by a Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015). The Vassiliou laboratory is also supported by the Kay Kendall Leukemia Fund and core funding from the Sanger Institute (WT098051).