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UTX-mediated Enhancer and Chromatin Remodeling Suppresses Myeloid Leukemogenesis Through Noncatalytic Inverse Regulation of ETS and GATA Programs

UTX-mediated Enhancer and Chromatin Remodeling Suppresses Myeloid Leukemogenesis Through Noncatalytic Inverse Regulation of ETS and GATA Programs

Malgorzata Gozdecka, Eshwar Meduri, Milena Mazan, Konstantinos Tzelepis, Monika Dudek, Andrew J Knights, Mercedes Pardo, Lu Yu, Jyoti S Choudhary, Emmanouil Metzakopian, Vivek Iyer, Haiyang Yun, Naomi Park, etc.

Nat Genet. 2018 Jun;50(6):883-894.

PMID: 29736013

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42416067	UTX human			Price

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