A Multi-Parameter Analysis of Cellular Coordination of Major Transcriptome Regulation Mechanisms

To understand cellular coordination of multiple transcriptome regulation mechanisms, we simultaneously measured transcription rate (TR), mRNA abundance (RA) and translation activity (TA). This revealed multiple quantitative insights. First, the genomic profiles of the three parameters are systematically different in key statistical features. Sequentially more genes exhibit extreme low or high expression values from TR to RA, then to TA. That is, because of cellular coordination of these regulatory mechanisms, sequentially higher levels of gene expression selectivity are achieved as genetic information flow from the genome to the proteome. Second, the contribution of the stabilization-by-translation regulatory mechanism to the cellular coordination process was assessed. The data enabled an estimation of mRNA stability, revealing a moderate but significant positive correlation between the estimated mRNA stability and translation activity. Third, the proportion of a mRNA occupied by un-translated regions (UTR) exhibits a negative relationship with the level of this correlation, and is thus a major determinant of the mode of regulation of the mRNA. High-UTR-proportion mRNAs tend to defy the stabilization-by-translation regulatory mechanism, staying out of the polysome but remaining stable; mRNAs with little UTRs largely follow this regulation. In summary, we quantitatively delineated the relationship among multiple transcriptome regulation parameters, i.e., cellular coordination of corresponding regulatory mechanisms. Simultaneous measurement of transcription rate with GRO-seq, mRNA abundance with RNA-seq and mRNA translation activity with polysome profiling

为阐明多转录组调控机制的细胞协同作用，我们同步测定了转录速率（transcription rate, TR）、mRNA丰度（mRNA abundance, RA）与翻译活性（translation activity, TA）。本研究获得多项量化发现：其一，三个参数的基因组谱在关键统计特征上存在系统性差异。从转录速率到mRNA丰度，再到翻译活性，呈现极端低或高表达值的基因数依次递增。换言之，得益于这些调控机制的细胞协同效应，随着遗传信息从基因组流向蛋白质组，基因表达的选择性水平也逐步提升。其二，我们评估了翻译介导的稳定调控机制在细胞协同过程中的贡献。基于本数据集可估算mRNA稳定性，结果显示估算得到的mRNA稳定性与翻译活性之间存在中度但显著的正相关关系。其三，mRNA的非翻译区（un-translated regions, UTR）占比与该相关程度呈负相关，因此UTR占比是决定mRNA调控模式的主要因素。UTR占比高的mRNA往往违背翻译介导的稳定调控机制：它们不进入多聚核糖体，但仍保持稳定；而UTR占比较低的mRNA则基本遵循该调控模式。综上，本研究定量阐明了多转录组调控参数间的关联，即对应调控机制的细胞协同效应。本研究采用GRO-seq检测转录速率、RNA-seq检测mRNA丰度，并通过多聚核糖体谱分析（polysome profiling）测定mRNA翻译活性。