title: Wilms tumor suppressor, WT1, suppresses epigenetic silencing of the β-catenin gene.
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.
authors.affiliation: From the Department of Human Genetics, McGill University, Montréal, Québec H3A 1B1 and.
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Akpa
authors.affiliation: the Department of Paediatrics, Montreal Children's Hospital Research Institute, Montréal, Québec H3Z 2Z3, Canada.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Iglesias
authors.affiliation: the Department of Paediatrics, Montreal Children's Hospital Research Institute, Montréal, Québec H3Z 2Z3, Canada.
authors.forename: Lee Lee
authors.initials: LL
authors.lastname: Chu
authors.affiliation: the Department of Paediatrics, Montreal Children's Hospital Research Institute, Montréal, Québec H3Z 2Z3, Canada.
authors.forename: Marta
authors.initials: M
authors.lastname: Cybulsky
authors.affiliation: the Department of Paediatrics, Montreal Children's Hospital Research Institute, Montréal, Québec H3Z 2Z3, Canada.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bravi
authors.affiliation: From the Department of Human Genetics, McGill University, Montréal, Québec H3A 1B1 and the Department of Paediatrics, Montreal Children's Hospital Research Institute, Montréal, Québec H3Z 2Z3, Canada paul.goodyer@mcgill.ca.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Goodyer
mesh_terms: D020816:Amino Acid Motifs; D000650:Amnion / Q000378:metabolism*; D002478:Cells, Cultured; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011247:Pregnancy; D013234:Stem Cells / Q000166:cytology; D025721:WT1 Proteins / Q000378:metabolism*; D009396:Wilms Tumor / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D006657:Histones; D025721:WT1 Proteins; C583751:WT1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: Enhancer of Zeste Homolog 2 (EZH2); Epigenetic Silencing; Epigenetics; Kidney; Nephrogenesis; Polycomb; Polycomb Repressor Complex; Wilms Tumor Suppressor 1 (WT1); Wnt Pathway; β-Catenin (B-catenin)