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

James R. Tollervey, Tomaz Curk, Boris Rogelj, Michael Briese, Matteo Cereda, Melis Kayikci, Julian Koenig, Tibor Hortobagyi, Agnes L. Nishimura, Vera Zupunski, Rickie Patani, Siddharthan Chandran, Gregor Rot, Blaz Zupan, Christopher E. Shaw, Jernej Ule

Research output: Contribution to journalArticlepeer-review

834 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)452 - 458
Number of pages7
JournalNature Neuroscience
Volume14
Issue number4
DOIs
Publication statusPublished - Apr 2011

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