Low overlap of transcription factor DNA binding and regulatory targets

Lakshmi Mahendrawada, Linda Warfield, Rafal Donczew and Steven Hahn ()
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Lakshmi Mahendrawada: Fred Hutchinson Cancer Center
Linda Warfield: Fred Hutchinson Cancer Center
Rafal Donczew: Fred Hutchinson Cancer Center
Steven Hahn: Fred Hutchinson Cancer Center

Nature, 2025, vol. 642, issue 8068, 796-804

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-08916-0

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