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- Title
Characterizing the RNA targets and position-dependent splicing regulation by TDP-43.
- Authors
Tollervey, James R; Curk, Tomaž; Rogelj, Boris; Briese, Michael; Cereda, Matteo; Kayikci, Melis; König, Julian; Hortobágyi, Tibor; Nishimura, Agnes L; Zupunski, Vera; Patani, Rickie; Chandran, Siddharthan; Rot, Gregor; Zupan, Blaž; Shaw, Christopher E; Ule, Jernej
- 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.
- Publication
Nature neuroscience, 2011, Vol 14, Issue 4, p452
- ISSN
1546-1726
- Publication type
Journal Article
- DOI
10.1038/nn.2778