Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Mol Syst Biol. 2020 Mar;16(3):e9275. doi: 10.15252/msb.20199275.
Different tissues express genes with particular codon usage and anticodon tRNA repertoires. However, the codon-anticodon co-adaptation in humans is not completely understood, nor is its effect on tissue-specific protein levels. Here, we first validated the accuracy of small RNA-seq for tRNA quantification across five human cell lines. We then analyzed the tRNA abundance of more than 8,000 tumor samples from TCGA, together with their paired mRNA-seq and proteomics data, to determine the Supply-to-Demand Adaptation. We thereby elucidate that the dynamic adaptation of the tRNA pool is largely related to the proliferative state across tissues. The distribution of such tRNA pools over the whole cellular translatome affects the subsequent translational efficiency, which functionally determines a condition-specific expression program both in healthy and tumor states. Furthermore, the aberrant translational efficiency of some codons in cancer, exemplified by ProCCA and GlyGGT, is associated with poor patient survival. The regulation of these tRNA profiles is partly explained by the tRNA gene copy numbers and their promoter DNA methylation.
不同的组织表达具有特殊密码子使用和反密码子 tRNA 库的基因。然而，人类的密码子-反密码子共适应还不完全清楚，其对组织特异性蛋白质水平的影响也不清楚。在这里，我们首先验证了小 RNA-seq 在五个人类细胞系中定量 tRNA 的准确性。然后，我们分析了 TCGA 中超过 8000 个肿瘤样本的 tRNA 丰度，以及它们配对的 mRNA-seq 和蛋白质组学数据，以确定供应-需求适应。由此阐明了 tRNA 库的动态适应在很大程度上与组织的增殖状态有关。这种 tRNA 池在整个细胞翻译组中的分布会影响随后的翻译效率，从而在健康和肿瘤状态下功能上决定了特定条件的表达程序。此外，一些密码子在癌症中的异常翻译效率，例如 ProCCA 和 GlyGGT，与患者的不良生存有关。这些 tRNA 谱的调节部分可以通过 tRNA 基因拷贝数及其启动子 DNA 甲基化来解释。
