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

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

OTHER RELATED OMICS DATASETS IN: PXD005011GSE86490

PROVIDER: PRJNA342026 | ENA |

REPOSITORIES: ENA

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

Project description: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.

2018-05-01 | GSE101307 | GEO

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

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

Project description: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.

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

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

Project description: Not available

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

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