The Transcription Factor WT1 Regulates Sequence-Specific TET2 Binding

TET enzymes mediate the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which acts as an epigenetic mark to modulate gene expression; however, the mechanisms that regulate TET binding to specific target genes remain unclear. Inactivating mutations in TET2 frequently occur in acute myelogenous leukemia (AML) in a mutually exclusive manner with gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2. Wang and colleagues found that mutations in TET2 and IDH1/2 were also mutually exclusive with mutations in the gene encoding the sequence-specific transcription factor Wilms tumor 1 (WT1), suggesting that these factors may function in the same pathway. Consistent with this idea, WT1 directly interacted with TET2 in AML cells and recruited TET2 to transcription start sites and CpG islands of WT1 target genes. This interaction was mediated primarily by the Cys-rich and double-strand β-helix (CD) domain of TET2 and the zinc-finger domain of WT1, and resulted in increased 5hmC levels and decreased 5mC levels at WT1 target gene promoters and activation of WT1 target gene expression. TET2-mediated induction of WT1 target genes was dependent on WT1 expression and the catalytic activity of TET2. In addition, WT1 was required for the ability of TET2 to inhibit leukemia cell proliferation and colony formation; combined depletion of both WT1 and TET2 did not additively stimulate cell proliferation, further supporting a TET2–WT1 tumor-suppressive pathway. Furthermore, a subset of recurrent AML-derived mutations targeting the TET2 CD domain abrogated TET2 binding to WT1 and impaired activation of WT1 target genes; overexpression of wild-type TET2, but not TET2 mutants unable to bind WT1, increased 5hmC levels in WT1 target gene promoters and suppressed leukemia cell proliferation. These findings, together with other recent studies, support a mechanism by which TET2 is recruited to specific genomic sequences and explain the mutually exclusive pattern of IDH1/2, WT1, and TET2 mutations in AML.

Wang Y, Xiao M, Chen X, Chen L, Xu Y, Lv L, et al. WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. Mol Cell 2015 Jan 15 [Epub ahead of print].