Journal Article

Pervasive isoform‐specific translational regulation via alternative transcription start sites in mammals

Chen, Wei, Hou, Jingyi, Quedenau, Claudia, Wang, Xi

2016

Overview

Transcription initiated at alternative sites can produce mRNA isoforms with different 5ʹUTRs, which are potentially subjected to differential translational regulation. However, the prevalence of such isoform‐specific translational control across mammalian genomes is currently unknown. By combining polysome profiling with high‐throughput mRNA 5ʹ end sequencing, we directly measured the translational status of mRNA isoforms with distinct start sites. Among 9,951 genes expressed in mouse fibroblasts, we identified 4,153 showed significant initiation at multiple sites, of which 745 genes exhibited significant isoform‐divergent translation. Systematic analyses of the isoform‐specific translation revealed that isoforms with longer 5ʹUTRs tended to translate less efficiently. Further investigation of cis‐ elements within 5ʹUTRs not only provided novel insights into the regulation by known sequence features, but also led to the discovery of novel regulatory sequence motifs. Quantitative models integrating all these features explained over half of the variance in the observed isoform‐divergent translation. Overall, our study demonstrated the extensive translational regulation by usage of alternative transcription start sites and offered comprehensive understanding of translational regulation by diverse sequence features embedded in 5ʹUTRs. Synopsis Polysome profiling combined with 5ʹ‐end sequencing in mouse fibroblasts shows pervasive isoform‐specific translational regulation via alternative transcription start sites (TSSs) and reveals 5′UTR sequence features linked to translational regulation. Isoform‐specific translational regulation is achieved through alternative TSS usage. Isoforms with longer 5ʹUTRs tend to have lower translational efficiency (TE). Systematic analyses of isoform‐specific translation offer new insights into the regulation by known sequence features and identifies novel regulatory sequence motifs. Quantitative models integrating all identified sequence features explain over half of the variance in the observed TE divergence between isoforms. Graphical Abstract Polysome profiling combined with 5ʹ‐end sequencing in mouse fibroblasts shows pervasive isoform‐specific translational regulation via alternative transcription start sites (TSSs) and reveals 5′UTR sequence features linked to translational regulation.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: 5' Untranslated Regions / alternative transcription start sites / Animals / cis‐regulatory elements / EMBO09 / EMBO17 / EMBO32 / Fibroblasts / Gene expression / Gene Expression Regulation / Gene regulation / Gene sequencing / Genes / Genomes / Isoforms / isoform‐divergent translation / Mammals / Mammals - genetics / Mice / NIH 3T3 Cells / Polyribosomes - genetics / Protein Biosynthesis / Proteins / Regulatory sequences / RNA, Messenger - genetics / Sequence Analysis, RNA - methods / Studies / Transcription / Transcription Initiation Site / Translation / translational regulation / Variables / Yeast