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<p>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 <i>Saccharomyces cerevisiae</i>, the&#xa0;main TF Pho4 relies on the co-TF Pho2 to regulate ~28 genes, whereas in the related pathogen <i>Candida glabrata</i>, Pho4 has reduced Pho2 dependence and regulates ~70 genes. We found <i>C. glabrata</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月18日

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  • 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

摘要

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.