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

• Published in: Nature neuroscience Vol. 14; no. 4; pp. 452 - 458
• Main Authors: Ule, Jernej, Tollervey, James R, Curk, Toma, Rogelj, Boris, Briese, Michael, Cereda, Matteo, Kayikci, Melis, König, Julian, Hortobágyi, Tibor, Nishimura, Agnes L, upunski, Vera, Patani, Rickie, Chandran, Siddharthan, Rot, Gregor, Zupan, Bla, Shaw, Christopher E
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2011; Nature Publishing Group
• Subjects: 631/208/1792; 631/208/200; 631/378/2583; 631/378/368/2430; Alternative Splicing - genetics; Amyotrophic lateral sclerosis; Analysis; Animal Genetics and Genomics; Bar codes; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Brain Chemistry - genetics; Brain research; Cell Line; Cell Line, Tumor; DNA binding proteins; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Gene Expression Regulation - genetics; Genetic aspects; Genomes; Humans; Neurobiology; Neurosciences; Physiological aspects; Protein Isoforms - genetics; Proteins; RNA; RNA Splicing - physiology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Untranslated - genetics; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; United Kingdom; United Kingdom > UK; Slovenia
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/nn.2778

TDP-43 is a RNA-binding protein that forms inclusion bodies in ALS. The authors show that TDP-43 preferentially binds long clusters of UG-rich sequences and that TDP-43 binding on pre-mRNAs influences alternative splicing. Many alternative mRNA isoforms regulated by TDP-43 encode proteins that regulate neuronal development or are implicated in neurological diseases. 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.