Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria.
PLoS One. 2012;7(6):e37906. doi: 10.1371/journal.pone.0037906. Epub 2012 Jun 7.
When grown in continuous culture, budding yeast cells tend to synchronize their respiratory activity to form a stable oscillation that percolates throughout cellular physiology and involves the majority of the protein-coding transcriptome. Oscillations in batch culture and at single cell level support the idea that these dynamics constitute a general growth principle. The precise molecular mechanisms and biological functions of the oscillation remain elusive. Fourier analysis of transcriptome time series datasets from two different oscillation periods (0.7 h and 5 h) reveals seven distinct co-expression clusters common to both systems (34% of all yeast ORF), which consolidate into two superclusters when correlated with a compilation of 1,327 unrelated transcriptome datasets. These superclusters encode for cell growth and anabolism during the phase of high, and mitochondrial growth, catabolism and stress response during the phase of low oxygen uptake. The promoters of each cluster are characterized by different nucleotide contents, promoter nucleosome configurations, and dependence on ATP-dependent nucleosome remodeling complexes. We show that the ATP:ADP ratio oscillates, compatible with alternating metabolic activity of the two superclusters and differential feedback on their transcription via activating (RSC) and repressive (Isw2) types of promoter structure remodeling. We propose a novel feedback mechanism, where the energetic state of the cell, reflected in the ATP:ADP ratio, gates the transcription of large, but functionally coherent groups of genes via differential effects of ATP-dependent nucleosome remodeling machineries. Besides providing a mechanistic hypothesis for the delayed negative feedback that results in the oscillatory phenotype, this mechanism may underpin the continuous adaptation of growth to environmental conditions.
在连续培养中，出芽酵母细胞倾向于同步其呼吸活动，形成一种稳定的振荡，这种振荡会渗透到细胞生理学的各个方面，并涉及到大多数蛋白质编码转录组。在分批培养和单细胞水平的振荡支持这样一种观点，即这些动力学构成了一种普遍的生长原则。振荡的确切分子机制和生物学功能仍然难以捉摸。对来自两个不同振荡周期（0.7 h 和 5 h）的转录组时间序列数据集进行傅里叶分析，揭示了两个系统中都存在的七个不同的共表达簇（占所有酵母 ORF 的 34%），当与 1327 个不相关的转录组数据集的汇编相关联时，这些簇可以合并成两个超级簇。这些超级簇在高氧摄取阶段编码细胞生长和合成代谢，在低氧摄取阶段编码线粒体生长、分解代谢和应激反应。每个簇的启动子都具有不同的核苷酸含量、启动子核小体构型，以及对 ATP 依赖性核小体重塑复合物的依赖性。我们表明，ATP:ADP 比在振荡，与两个超级簇的交替代谢活性以及通过激活（RSC）和抑制（Isw2）类型的启动子结构重塑对其转录的差异反馈兼容。我们提出了一种新的反馈机制，其中细胞的能量状态，反映在 ATP:ADP 比中，通过 ATP 依赖性核小体重塑机制的差异效应，对大但功能上一致的基因群的转录进行门控。除了为导致振荡表型的延迟负反馈提供一种机制假设外，这种机制可能是生长对环境条件的连续适应的基础。
