Gao Xiangwei, Wan Ji, Liu Botao, Ma Ming, Shen Ben, Qian Shu-Bing
Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA.
Graduate Field of Genetics, Genomics &Development, Cornell University, Ithaca, New York, USA.
Nat Methods. 2015 Feb;12(2):147-53. doi: 10.1038/nmeth.3208. Epub 2014 Dec 8.
Cells have evolved exquisite mechanisms to fine-tune the rate of protein synthesis in response to stress. Systemic mapping of start-codon positions and precise measurement of the corresponding initiation rate would transform our understanding of translational control. Here we present quantitative translation initiation sequencing (QTI-seq), with which the initiating ribosomes can be profiled in real time at single-nucleotide resolution. Resultant initiation maps not only delineated variations of start-codon selection but also highlighted a dynamic range of initiation rates in response to nutrient starvation. The integrated data set provided unique insights into principles of alternative translation and mechanisms controlling different aspects of translation initiation. With RiboTag mice, QTI-seq permitted tissue-specific profiling of initiating ribosomes in vivo. Liver cell-specific ribosome profiling uncovered a robust translational reprogramming of the proteasome system in fasted mice. Our findings illuminated the prevalence and dynamic nature of translational regulation pivotal to physiological adaptation in vivo.
细胞已经进化出精妙的机制来根据应激微调蛋白质合成的速率。起始密码子位置的系统图谱绘制以及相应起始速率的精确测量将改变我们对翻译控制的理解。在此,我们展示了定量翻译起始测序(QTI-seq),利用该技术可以在单核苷酸分辨率下实时分析起始核糖体。所得的起始图谱不仅描绘了起始密码子选择的变化,还突出了响应营养饥饿时起始速率的动态范围。整合的数据集为选择性翻译的原理以及控制翻译起始不同方面的机制提供了独特的见解。利用RiboTag小鼠,QTI-seq能够在体内对起始核糖体进行组织特异性分析。肝细胞特异性核糖体分析揭示了禁食小鼠中蛋白酶体系统强大的翻译重编程。我们的发现阐明了体内生理适应关键的翻译调控的普遍性和动态特性。