Tissue-specific regulation of gene expression via unproductive splicing

Eukaryotic gene expression is regulated post-transcriptionally by a universal mechanism called unproductive splicing, in which mRNA is triggered to degradation by the nonsense-mediated decay (NMD) pathway as a result of alternative splicing (AS). Only a few dozen unproductive splicing events (USEs) are documented, and many more remain to be identified. We performed an exhaustive search to catalog experimentally-validated and annotated USEs and monitored them in a panel of RNA-seq experiments from the Genotype-Tissue Expression Consortium by detecting concordant tissue-specific changes of gene expression levels and NMD isoform splicing rates. A juxtaposition of these data with transcriptomic responses to RNA-binding protein (RBP) expression perturbations from ENCODE Consortium and RBP footprinting data revealed a number of remarkable cases of regulated USEs with strong tissue-specific signatures, including previously proposed models of brain-specific regulation of PTBP2, DLG4, and GABBR1 mediated by PTBP1. Additionally, we identified a high-confidence set of 86 novel AS events generating NMD isoforms that are associated with tissue-specific downregulation of gene expression. We present a gallery of novel predicted USEs, including a PTBP1-controlled event in the DCLK2 gene, which may be responsible for its inhibition in non-neural tissues. These results greatly expand current knowledge on tissue-specific unproductive splicing and its regulation.