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.
More...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.
Overall design: Refer to individual Series
Less...| Accession | PRJNA342026; GEO: GSE86490 |
| Type | Umbrella project |
| Publications | Gozdecka M et al., "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 |
| Submission | Registration date: 6-Sep-2016
Department of Haematology, Wellcome TrustâMRC Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge |
| Relevance | Superseries |
Project Data:
| Resource Name | Number
of Links |
|---|
| Sequence data |
| SRA Experiments | 20 |
| Publications |
| PubMed | 1 |
| PMC | 1 |
| Other datasets |
| BioSample | 20 |
| GEO DataSets | 3 |
UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs encompasses the following 2 sub-projects:
| Project Type | Number of Projects |
| Epigenomics | 2 |
BioProject
accession | Organism | Title |
|---|
| PRJNA342032 | Mus musculus | UTX-mediated chromatin remodeling suppresses myeloid leukaemogenesis through non-catalytic inverse regulation of ETS and GATA transcriptional programs (ATAC-Seq) (Department of Haematology,...) | | PRJNA342033 | Mus musculus | UTX-mediated chromatin remodeling suppresses myeloid leukaemogenesis through non-catalytic inverse regulation of ETS and GATA transcriptional programs (ChIP-Seq) (Department of Haematology,...) |
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