美国弗雷德·哈钦森癌症中心Steven Hahn研究团队取得一项新突破。他们研究出转录因子DNA结合和调控靶点的低重叠。该项研究成果发表在2025年4月16日出版的《自然》上。

在这里，研究组整合了几乎完整的酵母TF的结合和表达目标的信息，并表明，与预期相反，很少有TF具有专用的激活或抑制作用，并且大多数TF具有双重功能。尽管几乎所有的蛋白质编码基因都受到一个或多个TF的调控，但他们的分析显示TF结合和基因调控之间的重叠有限。许多TF的快速耗竭也揭示了许多远离可检测到的TF结合位点的调控靶点，这提示了意想不到的调控机制。他们的研究提供了对TF功能的全面调查，并为单一细胞类型中表达的TF之间的相互作用以及它们如何促进复杂的基因调控程序提供了见解。

研究人员表示，DNA序列特异性转录因子（TFs）通过真核生物基因的增强子和启动子的调控位点调节转录和染色质结构。多个TF如何协同调节单个基因尚不清楚。在酵母中，大多数TF被认为是通过与上游激活序列的结合来调节转录的，这些激活序列位于被调节基因上游几百个碱基对内。尽管该模型已被证实适用于单个TF和特定基因，但尚未以系统的方式进行测试。

附：英文原文

Title: Low overlap of transcription factor DNA binding and regulatory targets

Author: Mahendrawada, Lakshmi, Warfield, Linda, Donczew, Rafal, Hahn, Steven

Issue&Volume: 2025-04-16

Abstract: DNA sequence-specific transcription factors (TFs) modulate transcription and chromatin architecture, acting from regulatory sites in enhancers and promoters of eukaryotic genes1,2. 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 gene3. 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.

DOI: 10.1038/s41586-025-08916-0

Source: https://www.nature.com/articles/s41586-025-08916-0