RESUMO
The SWI/SNF chromatin remodeling complex is a master regulator of developmental cell-fate decisions, although the key target pathways are poorly characterized. Here, we interrogated the contribution of the SWI/SNF subunit and tumor suppressor SNF5 to the regulation of developmental pathways using conditional mouse and cell culture models. We find that loss of SNF5 phenocopies ß-catenin hyperactivation and that SNF5 is essential for regulating Wnt/ß-catenin pathway target expression. These data provide insight into chromatin-based mechanisms that underlie developmental regulation and elucidate the emerging theme that mutation of this tumor suppressor complex can activate developmental pathways by uncoupling them from upstream control.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Genes Supressores de Tumor , Fatores de Transcrição/genética , Via de Sinalização Wnt , Animais , Sequência de Bases , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteínas Cromossômicas não Histona/deficiência , Proteínas de Ligação a DNA/deficiência , Regulação Neoplásica da Expressão Gênica , Humanos , Meduloblastoma/genética , Camundongos , Camundongos Transgênicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Tumor Rabdoide , Proteína SMARCB1 , Fator de Transcrição 4 , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismo , Transcriptoma , Células Tumorais CultivadasRESUMO
Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma. Predisposing germline loss-of-function DICER1 variants have been described. We sought to uncover additional contributors through whole exome sequencing of 15 tumor/normal pairs, followed by targeted resequencing, miRNA analysis and immunohistochemical analysis of additional tumors. In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain. 5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1. This work both defines a genetic interaction landscape with DICER1 mutation and provides evidence for alteration in miRNA transcripts as a consequence of DICER1 disruption in cancer.