title: Characterizing the RNA targets and position-dependent splicing regulation by TDP-43.
abstract: TDP-43 is a predominantly nuclear RNA-binding protein that forms inclusion bodies in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The mRNA targets of TDP-43 in the human brain and its role in RNA processing are largely unknown. Using individual nucleotide-resolution ultraviolet cross-linking and immunoprecipitation (iCLIP), we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo. Analysis of RNA binding by TDP-43 in brains from subjects with FTLD revealed that the greatest increases in binding were to the MALAT1 and NEAT1 noncoding RNAs. We also found that binding of TDP-43 to pre-mRNAs influenced alternative splicing in a similar position-dependent manner to Nova proteins. In addition, we identified unusually long clusters of TDP-43 binding at deep intronic positions downstream of silenced exons. A substantial proportion of alternative mRNA isoforms regulated by TDP-43 encode proteins that regulate neuronal development or have been implicated in neurological diseases, highlighting the importance of TDP-43 for the regulation of splicing in the brain.
authors.affiliation: Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Tollervey
authors.forename: Tomaž
authors.initials: T
authors.lastname: Curk
authors.forename: Boris
authors.initials: B
authors.lastname: Rogelj
authors.forename: Michael
authors.initials: M
authors.lastname: Briese
authors.forename: Matteo
authors.initials: M
authors.lastname: Cereda
authors.forename: Melis
authors.initials: M
authors.lastname: Kayikci
authors.forename: Julian
authors.initials: J
authors.lastname: König
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.forename: Agnes L
authors.initials: AL
authors.lastname: Nishimura
authors.forename: Vera
authors.initials: V
authors.lastname: Zupunski
authors.forename: Rickie
authors.initials: R
authors.lastname: Patani
authors.forename: Siddharthan
authors.initials: S
authors.lastname: Chandran
authors.forename: Gregor
authors.initials: G
authors.lastname: Rot
authors.forename: Blaž
authors.initials: B
authors.lastname: Zupan
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D001923:Brain Chemistry / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics; D012326:RNA Splicing / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D022661:RNA, Untranslated / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D022661:RNA, Untranslated; D016601:RNA-Binding Proteins