Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
Nucleic Acids Res. 2013 May;41(9):4743-54. doi: 10.1093/nar/gkt178. Epub 2013 Mar 21.
As a well-known phenomenon, total mRNAs poorly correlate to proteins in their abundances as reported. Recent findings calculated with bivariate models suggested even poorer such correlation, whereas focusing on the translating mRNAs (ribosome nascent-chain complex-bound mRNAs, RNC-mRNAs) subset. In this study, we analysed the relative abundances of mRNAs, RNC-mRNAs and proteins on genome-wide scale, comparing human lung cancer A549 and H1299 cells with normal human bronchial epithelial (HBE) cells, respectively. As discovered, a strong correlation between RNC-mRNAs and proteins in their relative abundances could be established through a multivariate linear model by integrating the mRNA length as a key factor. The R(2) reached 0.94 and 0.97 in A549 versus HBE and H1299 versus HBE comparisons, respectively. This correlation highlighted that the mRNA length significantly contributes to the translational modulation, especially to the translational initiation, favoured by its correlation with the mRNA translation ratio (TR) as observed. We found TR is highly phenotype specific, which was substantiated by both pathway analysis and biased TRs of the splice variants of BDP1 gene, which is a key transcription factor of transfer RNAs. These findings revealed, for the first time, the intrinsic and genome-wide translation modulations at translatomic level in human cells at steady-state, which are tightly correlated to the protein abundance and functionally relevant to cellular phenotypes.
作为一种众所周知的现象，总 mRNA 的丰度与其翻译产物的蛋白质丰度相关性较差，这一现象已被报道。最近的双变量模型研究结果表明，这种相关性甚至更差，而研究的重点是翻译中的 mRNA（核糖体新生链复合物结合的 mRNA，RNC-mRNA）亚组。在这项研究中，我们分别比较了人肺癌 A549 和 H1299 细胞与正常的人支气管上皮（HBE）细胞，在全基因组范围内分析了 mRNA、RNC-mRNA 和蛋白质的相对丰度。结果发现，通过整合关键因素 mRNA 长度，通过多元线性模型可以建立 RNC-mRNA 和蛋白质相对丰度之间的强相关性。在 A549 与 HBE 以及 H1299 与 HBE 的比较中，该相关性的 R²分别达到 0.94 和 0.97。这种相关性突出表明，mRNA 长度对翻译调控有重要贡献，特别是对翻译起始有重要贡献，这与其与 mRNA 翻译比（TR）的相关性一致。我们发现 TR 高度具有表型特异性，这一点得到了途径分析和 BDP1 基因剪接变异体的偏向 TR 的证实，BDP1 基因是转移 RNA 的关键转录因子。这些发现首次揭示了人细胞在稳定状态下在原子水平上的内在和全基因组翻译调控，这些调控与蛋白质丰度密切相关，与细胞表型具有功能相关性。
