UTX-mediated suppression of myeloid leukemogenesis is independent of its demethylase activity.
Major finding: UTX-mediated suppression of myeloid leukemogenesis is independent of its demethylase activity.
Mechanism: UTX loss activates oncogenic ETS programs and represses tumor-suppressive GATA programs.
Impact: UTX serves as a tumor suppressor in AML through its effects as a complex transcriptional regulator.
UTX is an H3K27-specific demethylase that is frequently subject to loss-of-function mutations in multiple tumor types including in leukemia. Accordingly, UTX has been described as a tumor suppressor, but the mechanisms by which it suppresses malignancy have not been fully elucidated. Gozdecka and colleagues found that Utx loss in hematopoietic stem and progenitor cells (HSPC) was sufficient to induce spontaneous acute myeloid leukemia (AML) in mice. UTX is X-linked, and the Y-chromosome homologue UTY, which lacks catalytic activity, was able to suppress leukemia induction in UTX-deficient male cells, suggesting that the catalytic activity of UTX is not required for its tumor suppressor function. Integrated RNA sequencing, chromatin immunoprecipitation sequencing, and assay for transposase accessible chromatin using sequencing in HSPCs from preleukemic Utx-/-, Utx-/Y, and Utx+/+ mice confirmed that H3K27 demethylase activity is not required for tumor suppression by UTX, with only minor changes in H3K27me3 observed upon UTX loss. Instead, UTX acted as both a transcriptional activator and transcriptional repressor. UTX loss activated oncogenic ETS transcriptional programs and, concurrently, repressed the tumor-suppressive GATA programs. UTX loss also resulted in a reduction of H3K4me1, an enhancer specifying chromatin mark that is deposited by the COMPASS complex, a known UTX interaction partner. Moreover, UTX did not interact directly with ETS factors or GATA2, but it did interact with chromatin remodeling proteins, including SMARCA4 and CHD4, with the UTX–SMARCA4 interaction maintaining chromatin accessibility at GATA-bound regions. As a consequence, UTX loss resulted in widespread bidirectional changes in chromatin accessibility and H3K27ac that facilitated the pioneering functions of ETS transcription factors in AML. Altogether, these findings elucidate a role for UTX in promoting chromatin remodeling and suppressing leukemogenesis independent of its demethylase activity.
Gozdecka M, Meduri E, Mazan M, Tzelepis K, Dudek M, Knights AJ, et al. UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. Nature Genet 2018 May 7 [Epub ahead of print].
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