Characterizing the RNA targets and position-dependent splicing regulation by TDP-43

James R Tollervey and Tomaz Curk and Boris Rogelj and Michael Briese and Matteo Cereda and Melis Kayikci and Julian Konig and Tibor Hortobágyi and Agnes L Nishimura and Vera Zupunski and Rickie Patani and Siddharthan Chandran and Gregor Rot and Blaz Zupan and Christopher E Shaw and Jernej Ule (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nature Neuroscience, 14 (4). pp. 452-458.

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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.

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