Journal Article

DKFZ-2018-00693

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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.DKFZ* ; Adams, D. ; Vassiliou, G. S. ; Huntly, B. J. P.

2018
Nature America New York, NY

This record in other databases:  

Please use a persistent id in citations: 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.

---

Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2018

---

Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 30 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

---