Divergence in a eukaryotic transcription factor’s co-TF dependence involves multiple intrinsically disordered regions

Lindsey F. Snyder, Emily M. O’Brien, Jia Zhao, Jinye Liang, Baylee J. Bruce, Yuning Zhang, Wei Zhu, Thomas H. Cassier, Nicholas J. Schnicker, Xu Zhou, Raluca Gordân and Bin Z. He ()
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Lindsey F. Snyder: University of Iowa
Emily M. O’Brien: University of Iowa
Jia Zhao: University of Iowa
Jinye Liang: University of Iowa
Baylee J. Bruce: University of Iowa
Yuning Zhang: Duke University
Wei Zhu: Duke University
Thomas H. Cassier: University of Iowa
Nicholas J. Schnicker: University of Iowa
Xu Zhou: Boston Children’s Hospital and Harvard Medical School
Raluca Gordân: Duke University
Bin Z. He: University of Iowa

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Combinatorial control by transcription factors (TFs) is central to eukaryotic gene regulation, yet its mechanism, evolution, and regulatory impact are not well understood. Here we use natural variation in the yeast phosphate starvation (PHO) response to examine the genetic basis and species variation in TF interdependence. In Saccharomyces cerevisiae, the main TF Pho4 relies on the co-TF Pho2 to regulate ~28 genes, whereas in the related pathogen Candida glabrata, Pho4 has reduced Pho2 dependence and regulates ~70 genes. We found C. glabrata Pho4 (CgPho4) binds the same motif with 3–4 fold higher affinity. Machine learning and yeast one-hybrid assay identify two intrinsically disordered regions (IDRs) in CgPho4 that boost its activation domain’s activity. In ScPho4, an IDR next to the DNA binding domain both allows for enhanced activity with Pho2 and inhibits activity without Pho2. This study reveals how IDR divergence drives TF interdependence evolution by influencing activation potential and autoinhibition.

Date: 2025
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DOI: 10.1038/s41467-025-59244-w

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