FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons

• Published in: Nature communications 2017-03, Vol.8 (1), p.14741-11, Article 14741
• Main Authors: Errichelli, Lorenzo, Dini Modigliani, Stefano, Laneve, Pietro, Colantoni, Alessio, Legnini, Ivano, Capauto, Davide, Rosa, Alessandro, De Santis, Riccardo, Scarfò, Rebecca, Peruzzi, Giovanna, Lu, Lei, Caffarelli, Elisa, Shneider, Neil A., Morlando, Mariangela, Bozzoni, Irene
• Format: Article
• Language: English
• Subjects: 38/1; 38/109; 38/39; 38/44; 38/77; 38/88; 38/89; 38/90; 38/91; 631/337/1645/1792; 631/337/2019; Amyotrophic lateral sclerosis; Animals; Biology; Biosynthesis; Cell Differentiation; Exons - genetics; Gene Deletion; Gene Expression Regulation; Genes; Humanities and Social Sciences; Introns - genetics; Mice; Motor Neurons - metabolism; Mouse Embryonic Stem Cells - cytology; multidisciplinary; Mutation; Mutation - genetics; Nervous system; Neurons; Pathogenesis; Protein Binding - genetics; Proteins; RNA - biosynthesis; RNA - genetics; RNA - metabolism; RNA polymerase; RNA Splicing - genetics; RNA, Circular; RNA-Binding Protein FUS - metabolism; Science; Science (multidisciplinary); Sequence Analysis, RNA; Spinal Cord - cytology; Stem cells
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14741

The RNA-binding protein FUS participates in several RNA biosynthetic processes and has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Here we report that FUS controls back-splicing reactions leading to circular RNA (circRNA) production. We identified circRNAs expressed in in vitro -derived mouse motor neurons (MNs) and determined that the production of a considerable number of these circRNAs is regulated by FUS. Using RNAi and overexpression of wild-type and ALS-associated FUS mutants, we directly correlate the modulation of circRNA biogenesis with alteration of FUS nuclear levels and with putative toxic gain of function activities. We also demonstrate that FUS regulates circRNA biogenesis by binding the introns flanking the back-splicing junctions and that this control can be reproduced with artificial constructs. Most circRNAs are conserved in humans and specific ones are deregulated in human-induced pluripotent stem cell-derived MNs carrying the FUS P525L mutation associated with ALS. The RNA binding protein FUS functions in several RNA biosynthetic processes and has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS). Here the authors show that FUS controls back-splicing reactions leading to circular RNA (circRNA) production in stem cell-derived motor neurons and that ALS-associated FUS mutations affect the biogenesis of circRNAs.