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

Nat Genet. 2018 Jun;50(6):883-894. doi: 10.1038/s41588-018-0114-z. Epub 2018 May 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Chromatin
  • GATA Transcription Factors
  • Histones
  • Proto-Oncogene Proteins c-ets
  • Histone Demethylases