title: Wilms Tumor Suppressor, WT1, Cooperates with MicroRNA-26a and MicroRNA-101 to Suppress Translation of the Polycomb Protein, EZH2, in Mesenchymal Stem Cells.
abstract: Hereditary forms of Wilms arise from developmentally arrested clones of renal progenitor cells with biallelic mutations of WT1; recently, it has been found that Wilms tumors may also be associated with biallelic mutations in DICER1 or DROSHA, crucial for miRNA biogenesis. We have previously shown that a critical role for WT1 during normal nephrogenesis is to suppress transcription of the Polycomb group protein, EZH2, thereby de-repressing genes in the differentiation cascade. Here we show that WT1 also suppresses translation of EZH2. All major WT1 isoforms induce an array of miRNAs, which target the 3' UTR of EZH2 and other Polycomb-associated transcripts. We show that the WT1(+KTS) isoform binds to the 5' UTR of EZH2 and interacts directly with the miRNA-containing RISC to enhance post-transcriptional inhibition. These observations suggest a novel mechanism through which WT1 regulates the transition from resting stem cell to activated progenitor cell during nephrogenesis. Our findings also offer a plausible explanation for the fact that Wilms tumors can arise either from loss of WT1 or loss of miRNA processing enzymes.
authors.affiliation: From the Department of Human Genetics, McGill University, Montréal, Québec H3A 1B1.
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Akpa
authors.affiliation: the Department of Pediatrics, Research Institute of the McGill University Health Center, Montréal, Québec H4A 3J1, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Iglesias
authors.affiliation: the Department of Pediatrics, Research Institute of the McGill University Health Center, Montréal, Québec H4A 3J1, Canada.
authors.forename: LeeLee
authors.initials: L
authors.lastname: Chu
authors.affiliation: the Department of Pediatrics, Research Institute of the McGill University Health Center, Montréal, Québec H4A 3J1, Canada.
authors.forename: Antonin
authors.initials: A
authors.lastname: Thiébaut
authors.affiliation: the Department of Pediatrics, Research Institute of the McGill University Health Center, Montréal, Québec H4A 3J1, Canada.
authors.forename: Ida
authors.initials: I
authors.lastname: Jentoft
authors.affiliation: the Department of Pediatrics, Research Institute of the McGill University Health Center, Montréal, Québec H4A 3J1, Canada.
authors.forename: Leah
authors.initials: L
authors.lastname: Hammond
authors.affiliation: the Department of Experimental Medicine, McGill University, Montreal, Québec H3A 1A3, and.
authors.forename: Elena
authors.initials: E
authors.lastname: Torban
authors.affiliation: From the Department of Human Genetics, McGill University, Montréal, Québec H3A 1B1, the Department of Pediatrics, Research Institute of the McGill University Health Center, Montréal, Québec H4A 3J1, Canada the Department of Experimental Medicine, McGill University, Montreal, Québec H3A 1A3, and paul.goodyer@mcgill.ca.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Goodyer
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000071221:Enhancer of Zeste Homolog 2 Protein; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000096:biosynthesis* / Q000235:genetics; D014176:Protein Biosynthesis; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism*; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000071221:Enhancer of Zeste Homolog 2 Protein; D035683:MicroRNAs; D063151:Polycomb Repressive Complex 2; D012334:RNA, Neoplasm; D025721:WT1 Proteins; C534072:MIRN101 microRNA, human; C528163:MIRN26 microRNA, human; C583751:WT1 protein, human; C498409:EZH2 protein, human
keywords: Argonaute; Enhancer of Zeste 2; Wilms tumor 1; dicer; kidney development; mesenchymal stem cells (MSCs); microRNA (miRNA); polycomb