title: Distinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses.
abstract: The RNA-binding protein (RBP) TAF15 is implicated in amyotrophic lateral sclerosis (ALS). To compare TAF15 function to that of two ALS-associated RBPs, FUS and TDP-43, we integrate CLIP-seq and RNA Bind-N-Seq technologies, and show that TAF15 binds to ∼4,900 RNAs enriched for GGUA motifs in adult mouse brains. TAF15 and FUS exhibit similar binding patterns in introns, are enriched in 3' untranslated regions and alter genes distinct from TDP-43. However, unlike FUS and TDP-43, TAF15 has a minimal role in alternative splicing. In human neural progenitors, TAF15 and FUS affect turnover of their RNA targets. In human stem cell-derived motor neurons, the RNA profile associated with concomitant loss of both TAF15 and FUS resembles that observed in the presence of the ALS-associated mutation FUS R521G, but contrasts with late-stage sporadic ALS patients. Taken together, our findings reveal convergent and divergent roles for FUS, TAF15 and TDP-43 in RNA metabolism.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore.
authors.forename: Katannya
authors.initials: K
authors.lastname: Kapeli
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Department of Bioinformatics and Systems Biology, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Pratt
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Anthony Q
authors.initials: AQ
authors.lastname: Vu
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Kasey R
authors.initials: KR
authors.lastname: Hutt
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Balaji
authors.initials: B
authors.lastname: Sundararaman
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Department of Neurosciences, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Batra
authors.affiliation: Department of Biology, MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Freese
authors.affiliation: Department of Biology, MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Lambert
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Department of Bioinformatics and Systems Biology, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Huelga
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, California 92010, USA.
authors.forename: Seung J
authors.initials: SJ
authors.lastname: Chun
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Tiffany Y
authors.initials: TY
authors.lastname: Liang
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California 95064, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Donohue
authors.affiliation: Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California 95064, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Shiue
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Haining
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Neurology, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Franca
authors.initials: F
authors.lastname: Cambi
authors.affiliation: Department of Neurology, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Kasarskis
authors.affiliation: Molecular Engineering Laboratory, A*STAR, Singapore 138673, Singapore.
authors.forename: Shawn
authors.initials: S
authors.lastname: Hoon
authors.affiliation: Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California 95064, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ares
authors.affiliation: Department of Biology, MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Burge
authors.affiliation: Department of Neurosciences, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ravits
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, California 92010, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore.|Department of Bioinformatics and Systems Biology, University of California at San Diego, La Jolla, California 92093, USA.|Molecular Engineering Laboratory, A*STAR, Singapore 138673, Singapore.
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D019295:Computational Biology / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts; D055785:Gene Knockdown Techniques; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D007438:Introns / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA / Q000379:methods; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D034702:RNA-Binding Protein FUS; D035381:TATA-Binding Protein Associated Factors; C000599550:FUS protein, human; C000599551:FUS protein, mouse; C102041:TAF15 protein, human; C000614666:TAF15 protein, mouse; C000598624:TARDBP protein, human; C578077:Tardbp protein, mouse