Wilms tumour suppressor, WT1, suppresses epigenetic silencing of the beta-catenin gene [Molecular Bases of Disease]

October 20th, 2014 by Akpa, M. M., Iglesias, D. M., Chu, L. L., Cybulsky, M., Bravi, C., Goodyer, P.

The mammalian kidney is derived from progenitor cells in intermediate mesoderm. During embryogenesis, progenitor cells expressing the Wilms tumour suppressor gene, WT1, are induced to differentiate in response to WNT signals from the ureteric bud. In hereditary Wilms tumours, clonal loss of WT1 precludes the beta-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 mesenchymal stem cells (amMSC), we show that exogenous WT1B represses EZH2 transcription. This leads to a dramatic decrease in the repressive lysine27 tri-methylation mark on histone H3 that silences beta-catenin gene expression. As a result, amMSC acquire responsiveness to WNT9b and increase expression of genes that mark the onset of nephron differentiation. Our observations suggest that bi-allelic loss of WT1 sustains the inhibitory histone methylation state that characterizes Wilms tumours.