title: FUS stimulates microRNA biogenesis by facilitating co-transcriptional Drosha recruitment.
abstract: 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.
authors.affiliation: Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Rome, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Morlando
authors.forename: Stefano
authors.initials: S
authors.lastname: Dini Modigliani
authors.forename: Giulia
authors.initials: G
authors.lastname: Torrelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rosa
authors.forename: Valerio
authors.initials: V
authors.lastname: Di Carlo
authors.forename: Elisa
authors.initials: E
authors.lastname: Caffarelli
authors.forename: Irene
authors.initials: I
authors.lastname: Bozzoni
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D047468:Immunoprecipitation; D035683:MicroRNAs / Q000096:biosynthesis*; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D009841:Oligonucleotides / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D043244:Ribonuclease III / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000502:physiology*
chemical_list: D002843:Chromatin; D035683:MicroRNAs; D009841:Oligonucleotides; D034702:RNA-Binding Protein FUS; C517918:DROSHA protein, human; D043244:Ribonuclease III