Wilms Tumor Suppressor, WT1, Suppresses Epigenetic Silencing of the β-Catenin Gene

The mammalian kidney is derived from progenitor cells in intermediate mesoderm. During embryogenesis, progenitor cells expressing the Wilms tumor suppressor gene, WT1, are induced to differentiate in response to WNT signals from the ureteric bud. In hereditary Wilms tumors, clonal loss of WT1 precludes the β-catenin pathway response and leads to precancerous nephrogenic rests. We hypothesized that WT1 normally primes progenitor cells for differentiation by suppressing the enhancer of zeste2 gene (EZH2), involved in epigenetic silencing of differentiation genes. In human amniotic fluid-derived mesenchymal stem cells, we show that exogenous WT1B represses EZH2 transcription. This leads to a dramatic decrease in the repressive lysine 27 trimethylation mark on histone H3 that silences β-catenin gene expression. As a result, amniotic fluid mesenchymal stem cells acquire responsiveness to WNT9b and increase expression of genes that mark the onset of nephron differentiation. Our observations suggest that biallelic loss of WT1 sustains the inhibitory histone methylation state that characterizes Wilms tumors.Hereditary Wilms tumors are preceded by WT1(−) clones with an inhibitory chromatin histone pattern established by EZH2.