The Yin and Yang of Yeast Transcription: Elements of a Global Feedback System between Metabolism and Chromatin

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.当以连续培养（continuous culture）方式培养时，酿酒酵母（budding yeast）细胞的呼吸活性会发生同步化，进而形成稳定的振荡；该振荡可遍及细胞生理过程，并覆盖绝大多数编码蛋白的转录组（protein-coding transcriptome）。分批培养（batch culture）与单细胞水平下观测到的振荡现象，支持此类动态变化属于普遍生长规律的观点。目前，该振荡的精确分子机制与生物学功能仍未明确。对两种不同振荡周期（0.7小时与5小时）的转录组时间序列数据集开展傅里叶分析（Fourier analysis），共得到7个在两个系统中均存在的独特共表达簇（co-expression cluster），覆盖全部酵母开放阅读框（Open Reading Frame, ORF）的34%；当将这些簇与1327个无关转录组数据集的整合集进行关联分析时，它们可聚合为两个超级簇（supercluster）。这两个超级簇分别在高氧摄取阶段参与细胞生长与合成代谢，在低氧摄取阶段参与线粒体生长、分解代谢与应激反应。每个簇的启动子（promoter）具有独特的核苷酸组成、核小体构型，且对ATP依赖型核小体重塑复合物（ATP-dependent nucleosome remodeling complex）的依赖性存在差异。我们证实ATP与ADP的比值（ATP:ADP ratio）存在振荡，这与两个超级簇交替的代谢活性，以及通过激活型（RSC）与抑制型（Isw2）启动子结构重塑复合物对二者转录产生的差异性反馈相吻合。我们提出一种全新的反馈机制：以ATP与ADP比值反映的细胞能量状态，可通过ATP依赖型核小体重塑机器的差异化作用，调控大型且功能一致的基因簇的转录。该机制不仅为产生振荡表型的延迟负反馈提供了力学假说，还可能是细胞生长持续适应环境条件的核心基础。