FUS stimulates microRNA biogenesis by facilitating co-transcriptional Drosha recruitment

• Published in: The EMBO journal 2012-12, Vol.31 (24), p.4502-4510
• Main Authors: Morlando, Mariangela, Dini Modigliani, Stefano, Torrelli, Giulia, Rosa, Alessandro, Di Carlo, Valerio, Caffarelli, Elisa, Bozzoni, Irene
• Format: Article
• Language: English
• Subjects: ALS; Amyotrophic lateral sclerosis; Biochemistry, Molecular Biology; Blotting, Western; Cell Line, Tumor; Chromatin; Chromatin - metabolism; Chromatin Immunoprecipitation; Drosha; Electrophoretic Mobility Shift Assay; EMBO24; EMBO36; FUS/TLS; Gene expression; Humans; Immunoprecipitation; Life Sciences; microRNA; MicroRNAs; MicroRNAs - biosynthesis; Molecular biology; Mutation; Neurons; Neurons - cytology; Neurons - physiology; Oligonucleotides; Oligonucleotides - genetics; Pathogenesis; Plasmids; Plasmids - genetics; Real-Time Polymerase Chain Reaction; Ribonuclease III; Ribonuclease III - metabolism; Ribonucleic acid; RNA; RNA-Binding Protein FUS; RNA-Binding Protein FUS - metabolism; Sarcoma; Synapses; Synapses - genetics; Synapses - physiology
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1038/emboj.2012.319

microRNA abundance has been shown to depend on the amount of the microprocessor components or, in some cases, on specific auxiliary co‐factors. In this paper, we show that the FUS/TLS (fused in sarcoma/translocated in liposarcoma) protein, associated with familial forms of Amyotrophic Lateral Sclerosis (ALS), contributes to the biogenesis of a specific subset of microRNAs. Among them, species with roles in neuronal function, differentiation and synaptogenesis were identified. We also show that FUS/TLS is recruited to chromatin at sites of their transcription and binds the corresponding pri‐microRNAs. Moreover, FUS/TLS depletion leads to decreased Drosha level at the same chromatin loci. Limited FUS/TLS depletion leads to a reduced microRNA biogenesis and we suggest a possible link between FUS mutations affecting nuclear/cytoplasmic partitioning of the protein and altered neuronal microRNA biogenesis in ALS pathogenesis. The RNA‐binding protein FUS/TLS is frequently mutated in ALS patients. FUS binds a subset of neuronal miRNA precursors and recruits the RNase III enzyme Drosha to enhance co‐transcriptional miRNA processing.