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| Item Type: | Article |
|---|---|
| Title: | UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs |
| Creators: |
Gozdecka, M., Meduri, E., Mazan, M., Tzelepis, K.  ORCID: https://orcid.org/0000-0002-4865-7648, Dudek, M., Knights, A.J., Pardo, M. ORCID: https://orcid.org/0000-0002-3477-9695, Yu, L. ORCID: https://orcid.org/0000-0001-8378-9112, Choudhary, J.S., Metzakopian, E., Iyer, V., Yun, H., Park, N., Varela, I. ORCID: https://orcid.org/0000-0002-0969-506X, Bautista, R., Collord, G. ORCID: https://orcid.org/0000-0003-1924-4411, Dovey, O., Garyfallos, D.A., De Braekeleer, E., Kondo, S., Cooper, J., Göttgens, B. ORCID: https://orcid.org/0000-0001-6302-5705, Bullinger, L. ORCID: https://orcid.org/0000-0002-5890-5510, Northcott, P.A., Adams, D., Vassiliou, G.S. ORCID: https://orcid.org/0000-0003-4337-8022 and Huntly, B.J.P. ORCID: https://orcid.org/0000-0003-0312-161X
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| 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. |
| Keywords: | Acute Myeloid Leukaemia, Cancer Stem Cells, Epigenetics, Animals, Mice |
| Source: | Nature Genetics |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Volume: | 50 |
| Number: | 6 |
| Page Range: | 883-894 |
| Date: | June 2018 |
| Official Publication: | https://doi.org/10.1038/s41588-018-0114-z |
| PubMed: | View item in PubMed |
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