UTX-mediated chromatin remodeling suppresses myeloid leukaemogenesis through non-catalytic inverse regulation of ETS and GATA transcriptional programs (ATAC-Seq). Mus musculus

The H3K27 lysine-specific demethylase UTX is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukaemogenesis through non-catalytic functions, a property it shares 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, 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 coordination of ATP-dependent chromatin remodelling and competition between UTX and ETS factors for binding at critical DNA-sequences. Collectively, our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via inhibition of oncogenic ETS and upregulation of tumour-suppressive GATA programmes. We propose that equivalent changes in tissue-specific oncogenic and tumour-suppressive transcriptional programmes operate in other UTX-mutated cancers. Overall design: ChIP-Seq analysis for two histone modifications (H3K27me3 and H3K27Ac) and ATAC-seq- comparison between mice deficient for the histone demethylase UTX (Utx-/-) vs wild type (Utx +/+).