Abstract
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.
Highlights
Hereditary Wilms tumors are preceded by WT1(Ϫ) clones with an inhibitory chromatin histone pattern established by EZH2
The amniotic mesenchymal stem cells (amMSC) express typical mesenchymal stem cell surface markers (CD90, CD105, CD73, and CD44) and the transcription factor, OSR1, characteristic of lineages derived from the mesoderm [15]
Maintenance of the stem cell state requires epigenetic silencing of genes involved in differentiation cascades [6, 17]
Summary
Hereditary Wilms tumors are preceded by WT1(Ϫ) clones with an inhibitory chromatin histone pattern established by EZH2. 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 -catenin gene expression. To escape the stem cell state, genes regulating the response to inductive signals must be made accessible by erasing the repressive histone H3K27me marks catalyzed by EZH2 (1, 4 – 6). Humans who inherit one mutant WT1 allele develop scattered Wilms tumor precursor lesions (“nephrogenic rests”) that form when the second WT1 allele is lost through sporadic somatic mutations These mutant WT1 clones lack WNT/catenin signaling activity and resemble embryonic progenitor cell clusters that have failed to undergo differentiation [12]. We show that suppression of EZH2 heightens responsiveness to an exogenous WNT9b signal and increases expression of genes involved in early stages of nephrogenesis
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