title: Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain.
abstract: Fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) are RNA-binding proteins pathogenetically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but it is not known if they regulate the same transcripts. We addressed this question using crosslinking and immunoprecipitation (iCLIP) in mouse brain, which showed that FUS binds along the whole length of the nascent RNA with limited sequence specificity to GGU and related motifs. A saw-tooth binding pattern in long genes demonstrated that FUS remains bound to pre-mRNAs until splicing is completed. Analysis of FUS(-/-) brain demonstrated a role for FUS in alternative splicing, with increased crosslinking of FUS in introns around the repressed exons. We did not observe a significant overlap in the RNA binding sites or the exons regulated by FUS and TDP-43. Nevertheless, we found that both proteins regulate genes that function in neuronal development.
authors.affiliation: Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK.
authors.forename: Boris
authors.initials: B
authors.lastname: Rogelj
authors.forename: Laura E
authors.initials: LE
authors.lastname: Easton
authors.forename: Gireesh K
authors.initials: GK
authors.lastname: Bogu
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Stanton
authors.forename: Gregor
authors.initials: G
authors.lastname: Rot
authors.forename: Tomaž
authors.initials: T
authors.lastname: Curk
authors.forename: Blaž
authors.initials: B
authors.lastname: Zupan
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Miha
authors.initials: M
authors.lastname: Modic
authors.forename: Nejc
authors.initials: N
authors.lastname: Haberman
authors.forename: James
authors.initials: J
authors.lastname: Tollervey
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Fujii
authors.forename: Toru
authors.initials: T
authors.lastname: Takumi
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005786:Gene Expression Regulation; D023061:Gene Order; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D059368:RNA Isoforms; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D059368:RNA Isoforms; D012322:RNA Precursors; D034702:RNA-Binding Protein FUS