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Divergent Roles of ALS-Linked Proteins FUS/TLS and TDP-43 Intersect In ART ic LE s Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs Clotilde Lagier-Tourenne1,2,9, Magdalini Polymenidou1,2,9, Kasey R Hutt2,3,9, Anthony Q Vu2,3, Michael Baughn4, Stephanie C Huelga2,3, Kevin M Clutario1,2, Shuo-Chien Ling1,2, Tiffany Y Liang2,3, Curt Mazur5, Edward Wancewicz5, Aneeza S Kim5, Andy Watt5, Sue Freier5, Geoffrey G Hicks6, John Paul Donohue7, Lily Shiue7, C Frank Bennett5, John Ravits4, Don W Cleveland1,2 & Gene W Yeo2,3,8 FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP-43 or FUS/TLS depletion in stem cell–derived human neurons and in TDP-43 aggregate–containing motor neurons in sporadic ALS, supporting a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS. ALS is an adult-onset neurodegenerative disorder that is characterized or diseased human16 CNS have been determined. Reducing TDP-43 expres- by premature degeneration of motor neurons, resulting in a progres- sion in the adult nervous system alters pre-mRNA splicing of >900 genes, sive, fatal paralysis. Approximately 10% of disease instances are familial, revealing an essential role for TDP-43 in sustaining the levels of RNAs with dominant mutations identified in several genes (reviewed in ref. 1). derived from very long intron–containing pre-mRNAs that are important A seminal discovery was the finding that the primarily nuclear RNA- for neuronal function15, some of which are reduced in human disease16. and DNA-binding protein TDP-43 is mislocalized in the cytoplasm of Using similar high-throughput sequencing and computational affected cells in essentially all sporadic ALS patients, where it forms approaches, we identified ~5,500 RNA targets of FUS/TLS in both insoluble, ubiquitinated inclusions2,3. TDP-43 pathology is also a promi- mouse and human brain. The expression levels of 610 genes were © All rights reserved. 2012 Inc. Nature America, nent feature of frontotemporal lobar degeneration (FTLD), which is now dependent on FUS/TLS, and only 112 of the genes were also depend- recognized as being genetically, clinically and pathologically linked to ent on TDP-43. Systematic comparison between the TDP-43– and ALS (reviewed in ref. 4). FUS/TLS-dependent targets identified RNAs with exceptionally long The discovery that dominant point mutations in TDP-43 cause introns and multiple binding sites for both TDP-43 and FUS/TLS. some instances of inherited ALS5–7 and FTLD was rapidly followed Depletion of FUS/TLS or TDP-43 in human neurons differentiated by the identification of mutations in another RNA- and DNA-binding from pluripotent stem cells confirmed the downregulation of long protein, FUS/TLS, that were responsible for an additional portion intron–containing TDP-43 and FUS/TLS targets. Several of these of inherited ALS8,9 and rare cases of FTLD. Cytoplasmic accumula- common targets were substantially reduced at the protein level in tion of FUS/TLS in the nervous system of patients with FUS/TLS affected post-mortem neurons of patients with sporadic ALS, thereby mutations8,9, and in some instances of FTLD in the absence of muta- identifying a common pathogenic pathway in motor neurons from tions10–12, disrupts its normal nuclear localization13. Whether the loss the misregulation of either TDP-43 or FUS/TLS. of FUS/TLS nuclear function or an acquired toxicity contributes to neuronal dysfunction in disease is unknown. RESULTS Both TDP-43 and FUS/TLS have been associated with multiple RNA targets of FUS/TLS in mouse and human brain nuclear and cytoplasmic steps of RNA processing (reviewed in ref. 14). FUS/TLS protein–RNA complexes cross-linked in vivo by ultraviolet Comprehensive maps of TDP-43–binding sites in RNAs of normal mouse15 light were efficiently immunoprecipitated using antibodies to three 1Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California, USA. 2Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, USA. 3Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA. 4Department of Neurosciences, University of California at San Diego, La Jolla, California, USA. 5Isis Pharmaceuticals, Carlsbad, California, USA. 6MB Institute of Cell Biology, University of Manitoba, Winnipeg, Canada. 7RNA Center, Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California, USA. 8Molecular Engineering Laboratory, A*STAR and Department of Biological Sciences, National University of Singapore, Singapore. 9These authors contributed equally to this work. Correspondence should be addressed to D.W.C. ([email protected]) or G.W.Y. ([email protected]). Received 12 June; accepted 6 September; published online 30 September 2012; doi:10.1038/nn.3230 NATURE NEUROSCIENCE ADVANCE ONLINE PUBLICATION 1 ART ic LE s Figure 1 FUS/TLS RNA targets in mouse and a Ab1 Ab3 Ab2 c human brain. (a) FUS/TLS protein domains Mouse neurofilament (Nefl) gene 1 kb Q/G/S/Y-rich region G-rich region E RRM R/G rich ZF R/G rich L used as antigens to generate antibodies Ab1, Mouse FUS GUGGU Ab2 and Ab3. Q/G/S/Y, glutamine, glycine, 70 serine, tyrosine; G, glycine; E, nuclear export b MNase MNase signal; RRM, RNA recognition motif; R/G, IP: FUS Ab1 IgG FUS Ab1 Pre Post FUS CLIP Ab1 UV: + + + + + – + + + + + + 0 arginine/glycine; ZF, zinc finger; L, nuclear 76 localization signal. (b) Autoradiograph of FUS/ 175 TLS protein–RNA complexes from mouse brain 80 FUS CLIP Ab2 immunoprecipitated with Ab1 and trimmed 50 0 with increasing concentrations of micrococcal 52 nuclease (MNase) (first panel). Complexes 46 highlighted by the red box were used for FUS CLIP Ab3 0 sequencing. Beads coated with IgG antibodies RNA Beads Supernatant 32 did not detect protein-RNA complexes (second Protein panel). Immunoprecipitated FUS/TLS-RNA FUS CLIP TDP-43 CLIP complexes migrated at the expected FUS/ d Uniquely mapped non redundant reads 0 TLS mobility (third panel), and no FUS/TLS 93,005,761 e Mouse FUS CLIP remained after immunoprecipitation (fourth In pre-mRNA Not in pre-mRNA panel). (c) FUS/TLS (green) and TDP-43 82,358,392 10,647,369 3 Human FUS CLIP (purple) binding to low molecular-weight 166,356 clusters Long ncRNA Pre-miRNA neurofilament subunit (Nefl) RNA. Vertical in 8,213 genes 1,620,506 62,067 2 red lines show the positions of GUGGU motifs. The scale bar represents the read coverage per f Distal Proximal 1 Motif enrichment base. (d) Flow chart illustrating reads analyzed 5′ UTR intron intron 3′ UTR from three CLIP-seq experiments to define 0 0 2 kb Exon 2 kb 100 200 300 400 500 FUS/TLS clusters. (e) Positional distribution –500 –400 –300 –200 –100 5% 1% 4% 5% 4% 1% of the GUGGU motif in FUS/TLS CLIP clusters 2% 4% Distance from FUS cluster peak (bp) 10% 12% 19% in human and mouse brain. (f) Percentages 30% 10% 25% 33% of TDP-43 and FUS/TLS CLIP clusters in 10% h 62% 51% 54% 58% TDP-43 7,951 genes pre-mRNAs regions as defined in the top panel. FUS 8,213 genes (g) FUS/TLS binding in human and mouse Mouse TDP-43 Mouse FUS Human FUS Size brain in orthologous exon 5 of the Fmr1 RNA. CLIP binding CLIP binding CLIP binding distribution Strict overlap Any cluster 2,727 genes 6,312 genes (h) Venn diagrams showing genes with TDP-43 and FUS/TLS CLIP clusters overlapping by at 0.5 kb 200 bp least one nucleotide (left) or genes with both g Mouse fragile X mental retardation gene (Fmr1) i Glutamate receptor 3 (Gria3) gene TDP-43– and FUS/TLS-binding sites (right). GUGGU 377 377 (i) Overlapping TDP-43 and FUS/TLS clusters Mouse FUS CLIP in neighboring, but distinct, intronic positions 0 FUS CLIP in the Gria3 pre-mRNA. 176 0 176 Human FUS CLIP 0 distinct regions of FUS/TLS (Fig. 1a,b and TDP-43 CLIP Human fragile X mental retardation gene (Fmr1) 0 © All rights reserved. 2012 Inc. Nature America, Supplementary Fig. 1a,b), resulting in a sub- stantial reduction of FUS/TLS from mouse brain lysates (Fig. 1b and Supplementary Fig. 1c). Each antibody pre- mapped to annotated long noncoding RNAs (lncRNAs; Fig. 1d and cipitated complexes with the expected mobility for a single FUS/TLS Supplementary Fig. 1f). Using a cluster-finding algorithm with gene- molecule bound to RNA, as well as some lower mobility complexes specific thresholds that account for pre-mRNA length and variable (Supplementary Fig. 1a,b). No complexes were immunoprecipitated expression levels15,17, we identified 166,356 FUS/TLS-binding sites when using nonspecific IgG or in the absence of ultraviolet cross- (with minimally 28 reads each and an average of 92 reads) in 8,213 linking (Fig.
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