Data-driven identification of inherent features of eukaryotic stress-responsive genes

Virtually all living organisms are challenged by changes in their environment, such as sudden increases in osmolarity. To survive, cells have developed stress-responsive mechanisms that tune functions such as metabolism and gene expression. The response of Saccharomyces cerevisiae to osmostress includes a massive reprogramming of gene expression. Identifying the inherent features of stress-responsive genes is of significant interest for understanding the basic principles underlying the rewiring of gene expression upon stress. Here we generated a comprehensive catalog of osmotress-responsive genes from 5 independent RNA-seq experiments. We explored 30 features of yeast genes and found that 25 (83.34%) were distinct in osmostress-responsive genes. We then identified a subset of 13 non-redundant minimal osmostress gene traits and used statistical modeling to generate a ranking of the most stress-predictive features. Our findings reveal that the most relevant features of osmostress-responsive genes are the number of transcription factors targeting a gene and gene conservation. The same features that define yeast osmostress-responsive genes can also be used to predict osmostress-responsive genes in humans, although the most predictive features in humans are GC content and mRNA half-life. Our study provides a holistic understanding of the basic principles of the regulation of stress-responsive gene expression across eukaryotes.几乎所有活生物体都会面临环境变化带来的挑战，例如渗透压（osmolarity）的骤然升高。为存活下去，细胞演化出了应激响应机制，以此调控代谢与基因表达等核心生理功能。酿酒酵母（Saccharomyces cerevisiae）对渗透压应激（osmostress）的响应包含大规模的基因表达重编程。解析应激响应基因的内在特征，对于理解应激状态下基因表达重编程的底层基本原理具有重要学术价值。本研究基于5组独立的RNA测序（RNA-seq）实验，构建了一套完整的渗透压应激响应基因（osmostress-responsive genes）目录。我们针对酵母基因的30项特征展开系统性分析，发现其中25项（占比83.34%）在渗透压应激响应基因中呈现显著差异。随后我们筛选出13项非冗余的核心渗透压应激基因特征子集，并通过统计建模生成了最具应激预测能力的特征排序结果。本研究结果显示，渗透压应激响应基因最具相关性的特征为靶向该基因的转录因子（transcription factor）数量与基因保守性。尽管在人类中最具预测能力的特征为GC含量与mRNA半衰期，但用于界定酵母渗透压应激响应基因的上述特征，同样可用于预测人类的渗透压应激响应基因。本研究为真核生物（eukaryotes）应激响应基因表达调控的底层基本原理提供了全面的认知框架。