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

TitleCharacterizing the RNA targets and position-dependent splicing regulation by TDP-43.
Publication TypeJournal Article
Year of Publication2011
AuthorsTollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M, König J, Hortobágyi T, Nishimura AL, Zupunski V, Patani R, Chandran S, Rot G, Zupan B, Shaw CE, Ule J
JournalNat Neurosci
Date Published2011 Apr
KeywordsAlternative Splicing, Brain Chemistry, Cell Line, Cell Line, Tumor, DNA-Binding Proteins, Gene Expression Regulation, Humans, Protein Isoforms, RNA Splicing, RNA, Messenger, RNA, Untranslated, RNA-Binding Proteins

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.

Alternate JournalNat. Neurosci.
PubMed ID21358640
PubMed Central IDPMC3108889
Grant List089701 / / Wellcome Trust / United Kingdom
206726 / / European Research Council / International
MC_U105185858 / / Medical Research Council / United Kingdom
U.1051.04.028.00001.01 (85858) / / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom
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