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; Bin Z He

doi:10.1038/s41467-025-59244-w

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

Nat Commun. 2025 Jun 18;16(1):5340. doi: 10.1038/s41467-025-59244-w.

Authors

Lindsey F Snyder¹, Emily M O'Brien², Jia Zhao^{2

3}, Jinye Liang², Baylee J Bruce¹, Yuning Zhang^{4

5}, Wei Zhu⁶, Thomas H Cassier², Nicholas J Schnicker^{7

8}, Xu Zhou⁹, Raluca Gordân^{4

6

10

11

12}, Bin Z He^{13

14}

Affiliations

¹ Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA, USA.
² Department of Biology, University of Iowa, Iowa City, IA, USA.
³ Laboratory of Immunophysiology, The Ragon Institute of Mass General, MIT, and Harvard; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Department of Biostatistics & Bioinformatics, Duke University, Durham, NC, USA.
⁵ Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
⁶ Department of Molecular Genetics & Microbiology, Duke University, Durham, NC, USA.
⁷ Protein and Crystallography Facility, University of Iowa, Iowa City, IA, USA.
⁸ Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.
⁹ Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Computer Science, Duke University, Durham, NC, USA.
¹¹ Department of Cell Biology, Duke University, Durham, NC, USA.
¹² Department of Genomics and Computational Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
¹³ Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA, USA. bin-he@uiowa.edu.
¹⁴ Department of Biology, University of Iowa, Iowa City, IA, USA. bin-he@uiowa.edu.

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.

MeSH terms

Candida glabrata* / genetics
Candida glabrata* / metabolism
DNA-Binding Proteins
Gene Expression Regulation, Fungal
Intrinsically Disordered Proteins* / chemistry
Intrinsically Disordered Proteins* / genetics
Intrinsically Disordered Proteins* / metabolism
Phosphates / metabolism
Protein Binding
Saccharomyces cerevisiae Proteins* / chemistry
Saccharomyces cerevisiae Proteins* / genetics
Saccharomyces cerevisiae Proteins* / metabolism
Saccharomyces cerevisiae* / genetics
Saccharomyces cerevisiae* / metabolism
Transcription Factors* / chemistry
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Saccharomyces cerevisiae Proteins
Transcription Factors
Intrinsically Disordered Proteins
PHO4 protein, S cerevisiae
Phosphates
DNA-Binding Proteins

Abstract

MeSH terms

Substances

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