Mahendrawada Lakshmi, Warfield Linda, Donczew Rafal, Hahn Steven
Fred Hutchinson Cancer Center, Seattle, WA, USA.
Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Nature. 2025 Apr 16. doi: 10.1038/s41586-025-08916-0.
DNA sequence-specific transcription factors (TFs) modulate transcription and chromatin architecture, acting from regulatory sites in enhancers and promoters of eukaryotic genes. How multiple TFs cooperate to regulate individual genes is still unclear. In yeast, most TFs are thought to regulate transcription via binding to upstream activating sequences, which are situated within a few hundred base pairs upstream of the regulated gene. Although this model has been validated for individual TFs and specific genes, it has not been tested in a systematic way. Here we integrated information on the binding and expression targets for the near-complete set of yeast TFs and show that, contrary to expectations, there are few TFs with dedicated activator or repressor roles, and that most TFs have a dual function. Although nearly all protein-coding genes are regulated by one or more TFs, our analysis revealed limited overlap between TF binding and gene regulation. Rapid depletion of many TFs also revealed many regulatory targets that were distant from detectable TF binding sites, suggesting unexpected regulatory mechanisms. Our study provides a comprehensive survey of TF functions and offers insights into interactions between the set of TFs expressed in a single cell type and how they contribute to the complex programme of gene regulation.
DNA序列特异性转录因子（TFs）可调节转录和染色质结构，作用于真核基因增强子和启动子中的调控位点。多个转录因子如何协同调控单个基因仍不清楚。在酵母中，大多数转录因子被认为通过与上游激活序列结合来调控转录，这些序列位于被调控基因上游几百个碱基对之内。尽管该模型已针对单个转录因子和特定基因得到验证，但尚未进行系统测试。在此，我们整合了酵母转录因子近乎完整集合的结合和表达靶点信息，结果表明，与预期相反，几乎没有具有专门激活或抑制作用的转录因子，且大多数转录因子具有双重功能。尽管几乎所有蛋白质编码基因都受一个或多个转录因子调控，但我们的分析揭示了转录因子结合与基因调控之间的重叠有限。许多转录因子的快速消耗还揭示了许多远离可检测转录因子结合位点的调控靶点，这表明存在意想不到的调控机制。我们的研究对转录因子功能进行了全面概述，并深入探讨了单一细胞类型中表达的转录因子集合之间的相互作用，以及它们如何促成复杂的基因调控程序。
