Global variability in gene expression and alternative splicing is modulated by mitochondrial content.

Noise in gene expression is a main determinant of phenotypic variability. Increasing experimental evidence suggests that genome-wide cellular constraints largely contribute to the heterogeneity observed in gene products. It is still unclear, however, which global factors mostly affect gene expression noise, and to which extent. Since eukaryotic gene expression is an energy demanding process, differences in the energy budget of each cell could determine gene expression differences. Here, we quantify the contribution of mitochondrial variability (a natural source of ATP variation) to global variability in gene expression. We find that changes in mitochondrial content can account for ~50% of the variability observed in protein levels. This is the combined result of the effect of mitochondria dosage on transcription and translation apparatus content and activities. Moreover, we find that mitochondrial levels have a large impact on alternative splicing, thus modulating both the abundance and type of mRNAs. A simple mathematical model where mitochondrial content simultaneously affects transcription rate and splicing site choice can explain the alternative splicing data. The results of this study show that mitochondrial content (and/or probably function) influence mRNA abundance, translation and alternative splicing which ultimately impacts on cellular phenotype.

基因表达中的噪声是表型变异（phenotypic variability）的主要决定因素。越来越多的实验证据表明，全基因组层面的细胞约束在很大程度上促成了基因产物中观测到的异质性。然而，目前仍不清楚哪些全局因素对基因表达噪声的影响最为显著，以及其影响程度究竟几何。由于真核生物基因表达（eukaryotic gene expression）是一种耗能过程，不同细胞间的能量预算差异或许决定了基因表达的差异。本研究量化了线粒体变异（mitochondrial variability）——三磷酸腺苷（ATP）变异的天然来源——对基因表达全局变异的贡献。我们发现，线粒体含量（mitochondrial content）的变化可解释约50%的蛋白质水平（protein levels）观测变异。这一结果是线粒体剂量对转录与翻译装置（transcription and translation apparatus）的含量及活性产生影响的共同作用结果。此外，我们发现线粒体水平对可变剪接（alternative splicing）具有显著调控作用，进而影响信使RNA（messenger RNA, mRNA）的丰度与类型。一个简单的数学模型（mathematical model）——线粒体含量同时影响转录速率（transcription rate）与剪接位点选择（splicing site choice）——可合理解释可变剪接实验数据。本研究结果表明，线粒体含量（或可能还包括其功能）可影响mRNA丰度、翻译过程与可变剪接，最终对细胞表型产生影响。