Ribosome profiling in mammalian tissue reveals extensive translational regulation in the cardiometabolic syndrome

The extent of translational control of gene expression in mammalian tissues remains largely unknown. We analyzed genome-wide RNA expression and ribosome occupancies in heart and liver tissues to investigate strain-specific translational regulation in disease-relevant tissues in the rat. For the most part, transcriptional variation is equally apparent at the translational level and there is limited evidence of translational buffering. In addition we also find hundreds of strain-specific differences in gene expression at the level of translation only that are influencing protein levels beyond transcriptional regulation. By integrating genetic, transcriptional and translational datasets we identify distinct signatures in 3’UTR variation, RNA binding protein motifs, and miRNA expression associated with translational regulation. We document novel and extensive translational control of important metabolic and cardiac genes. Several genes associated with heart and liver traits in human genome wide association studies are regulated at the translational level. Capturing inter-individual differences in the translated genome will lead to new insights into the genes and regulatory pathways underlying disease phenotypes.

哺乳动物组织中基因表达的翻译调控程度，目前仍在很大程度上未被阐明。我们对大鼠心脏与肝脏组织开展了全基因组RNA表达及核糖体占据情况分析，以探究疾病相关组织中品系特异性的翻译调控机制。整体而言，转录水平的变异在翻译层面同样显著，且仅存在有限的翻译缓冲证据。此外，我们还发现了数百个仅在翻译层面存在品系特异性表达差异的基因，这些差异可在转录调控之外影响蛋白质水平。通过整合遗传、转录组及翻译组数据集，我们鉴定出与翻译调控相关的3'非翻译区（3'UTR）变异、RNA结合蛋白基序以及microRNA (miRNA)表达的特征性信号。我们证实了重要代谢与心脏相关基因存在新颖且广泛的翻译调控现象。在人类全基因组关联研究中与心脏、肝脏性状相关的多个基因，其表达受到翻译层面的调控。解析翻译组层面的个体间差异，将为疾病表型背后的基因及调控通路研究带来新的认知。