The ribosome-engaged landscape of alternative splicing

• Published in: Nature structural & molecular biology Vol. 23; no. 12; pp. 1117 - 1123
• Main Authors: Weatheritt, Robert J, Sterne-Weiler, Timothy, Blencowe, Benjamin J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2016; Nature Publishing Group
• Subjects: 5' Untranslated Regions; 631/208/1792; 631/208/212; 631/337/574/1789; Alternative Splicing; Analysis; Animals; Biochemistry; Biological Microscopy; Cell Cycle; Comparative analysis; Gene sequencing; Genomics; High-Throughput Nucleotide Sequencing; Humans; Introns; Life Sciences; Mammals; Membrane Biology; Mice; Molecular biology; Protein Structure; Ribonucleic acid; Ribosomes; Ribosomes - genetics; RNA; RNA sequencing; RNA splicing; RNA, Messenger - genetics; RNA, Ribosomal - genetics; Sequence Analysis, RNA; Splicing; Transcription factors; United States
• ISSN: 1545-9993; 1545-9985; 1545-9985
• DOI: 10.1038/nsmb.3317

Comparative analysis of RNA-seq and ribosome profiling data show that a major fraction of exon-skipping events in transcripts with medium-to-high abundance are engaged by ribosomes and therefore are likely to be translated. High-throughput RNA sequencing (RNA-seq) has revealed an enormous complexity of alternative splicing (AS) across diverse cell and tissue types. However, it is currently unknown to what extent repertoires of splice-variant transcripts are translated into protein products. Here, we surveyed AS events engaged by the ribosome. Notably, at least 75% of human exon-skipping events detected in transcripts with medium-to-high abundance in RNA-seq data were also detected in ribosome profiling data. Furthermore, relatively small subsets of functionally related splice variants are engaged by ribosomes at levels that do not reflect their absolute abundance, thus indicating a role for AS in modulating translational output. This mode of regulation is associated with control of the mammalian cell cycle. Our results thus suggest that a major fraction of splice variants is translated and that specific cellular functions including cell-cycle control are subject to AS-dependent modulation of translation output.