Divergence in a eukaryotic transcription factor’s co-TF dependence involves multiple intrinsically disordered regions
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59244-w |
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| _version_ | 1849686036216545280 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Lindsey F. Snyder |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b6a36a52dd9041da8840b2b77c660f3f |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b6a36a52dd9041da8840b2b77c660f3f2025-08-20T03:22:53ZengNature PortfolioNature Communications2041-17232025-06-0116111610.1038/s41467-025-59244-wDivergence in a eukaryotic transcription factor’s co-TF dependence involves multiple intrinsically disordered regionsLindsey F. Snyder0Emily M. O’Brien1Jia Zhao2Jinye Liang3Baylee J. Bruce4Yuning Zhang5Wei Zhu6Thomas H. Cassier7Nicholas J. Schnicker8Xu Zhou9Raluca Gordân10Bin Z. He11Interdisciplinary Graduate Program in Genetics, University of IowaDepartment of Biology, University of IowaDepartment of Biology, University of IowaDepartment of Biology, University of IowaInterdisciplinary Graduate Program in Genetics, University of IowaDepartment of Biostatistics & Bioinformatics, Duke UniversityDepartment of Molecular Genetics & Microbiology, Duke UniversityDepartment of Biology, University of IowaProtein and Crystallography Facility, University of IowaDepartment of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital and Harvard Medical SchoolDepartment of Biostatistics & Bioinformatics, Duke UniversityInterdisciplinary Graduate Program in Genetics, University of IowaAbstract 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.https://doi.org/10.1038/s41467-025-59244-w |
| spellingShingle | 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 Divergence in a eukaryotic transcription factor’s co-TF dependence involves multiple intrinsically disordered regions Nature Communications |
| title | Divergence in a eukaryotic transcription factor’s co-TF dependence involves multiple intrinsically disordered regions |
| title_full | Divergence in a eukaryotic transcription factor’s co-TF dependence involves multiple intrinsically disordered regions |
| title_fullStr | Divergence in a eukaryotic transcription factor’s co-TF dependence involves multiple intrinsically disordered regions |
| title_full_unstemmed | Divergence in a eukaryotic transcription factor’s co-TF dependence involves multiple intrinsically disordered regions |
| title_short | Divergence in a eukaryotic transcription factor’s co-TF dependence involves multiple intrinsically disordered regions |
| title_sort | divergence in a eukaryotic transcription factor s co tf dependence involves multiple intrinsically disordered regions |
| url | https://doi.org/10.1038/s41467-025-59244-w |
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