{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:43:15Z","timestamp":1791405795058,"version":"4.3.3"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000057","name":"U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM137831"],"award-info":[{"award-number":["R35GM137831"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM008629"],"award-info":[{"award-number":["T32GM008629"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM1454441"],"award-info":[{"award-number":["T32GM1454441"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                    , the\u00a0main TF Pho4 relies on the co-TF Pho2 to regulate ~28 genes, whereas in the related pathogen\n                    <jats:italic>Candida glabrata<\/jats:italic>\n                    , Pho4 has reduced Pho2 dependence and regulates ~70 genes. We found\n                    <jats:italic>C. glabrata<\/jats:italic>\n                    Pho4 (CgPho4) binds the same motif with 3\u20134 fold higher affinity. Machine learning and yeast one-hybrid assay identify two intrinsically disordered regions (IDRs) in CgPho4 that boost its activation domain\u2019s 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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-025-59244-w","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T12:43:30Z","timestamp":1750250610000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Divergence in a eukaryotic transcription factor\u2019s co-TF dependence involves multiple intrinsically disordered regions"],"prefix":"10.1038","volume":"16","author":[{"given":"Lindsey F.","family":"Snyder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily M.","family":"O\u2019Brien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4161-9307","authenticated-orcid":false,"given":"Jinye","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baylee J.","family":"Bruce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuning","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Cassier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5189-4943","authenticated-orcid":false,"given":"Nicholas J.","family":"Schnicker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1692-6823","authenticated-orcid":false,"given":"Xu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raluca","family":"Gord\u00e2n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3072-6238","authenticated-orcid":false,"given":"Bin Z.","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"59244_CR1","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1534\/genetics.112.143370","volume":"192","author":"AJ Stewart","year":"2012","unstructured":"Stewart, A. J., Hannenhalli, S. & Plotkin, J. B. Why transcription factor binding sites are ten nucleotides long. Genetics 192, 973\u2013985 (2012).","journal-title":"Genetics"},{"key":"59244_CR2","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1016\/j.cell.2008.05.024","volume":"133","author":"MF Berger","year":"2008","unstructured":"Berger, M. F. et al. Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell 133, 1266\u20131276 (2008).","journal-title":"Cell"},{"key":"59244_CR3","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1016\/j.molcel.2011.05.025","volume":"42","author":"X Zhou","year":"2011","unstructured":"Zhou, X. & O\u2019Shea, E. K. Integrated approaches reveal determinants of genome-wide binding and function of the transcription factor Pho4. Mol. Cell 42, 826\u2013836 (2011).","journal-title":"Mol. Cell"},{"key":"59244_CR4","doi-asserted-by":"publisher","first-page":"645","DOI":"10.3389\/fmicb.2016.00645","volume":"7","author":"J Merhej","year":"2016","unstructured":"Merhej, J. et al. A network of paralogous stress response transcription factors in the human pathogen candida glabrata. Front. Microbiol. 7, 645 (2016).","journal-title":"Front. Microbiol."},{"key":"59244_CR5","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11416-1","volume":"10","author":"C S\u00e1nchez-Higueras","year":"2019","unstructured":"S\u00e1nchez-Higueras, C. et al. In vivo Hox binding specificity revealed by systematic changes to a single cis regulatory module. Nat. Commun. 10, 3597 (2019).","journal-title":"Nat. Commun."},{"key":"59244_CR6","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.1016\/j.cell.2011.10.053","volume":"147","author":"M Slattery","year":"2011","unstructured":"Slattery, M. et al. Cofactor binding evokes latent differences in DNA binding specificity between Hox proteins. Cell 147, 1270\u20131282 (2011).","journal-title":"Cell"},{"key":"59244_CR7","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.tig.2014.04.002","volume":"30","author":"A-L Todeschini","year":"2014","unstructured":"Todeschini, A.-L., Georges, A. & Veitia, R. A. Transcription factors: specific DNA binding and specific gene regulation. Trends Genet. 30, 211\u2013219 (2014).","journal-title":"Trends Genet."},{"key":"59244_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00782-6","author":"\u017d Avsec","year":"2021","unstructured":"Avsec, \u017d. et al. Base-resolution models of transcription-factor binding reveal soft motif syntax. Nat. Genet. https:\/\/doi.org\/10.1038\/s41588-021-00782-6 (2021).","journal-title":"Nat. Genet."},{"key":"59244_CR9","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1126\/science.1058312","volume":"292","author":"KA Guss","year":"2001","unstructured":"Guss, K. A., Nelson, C. E., Hudson, A., Kraus, M. E. & Carroll, S. B. Control of a genetic regulatory network by a selector gene. Science 292, 1164\u20131167 (2001).","journal-title":"Science"},{"key":"59244_CR10","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1016\/j.cell.2016.11.033","volume":"167","author":"Y-S Ang","year":"2016","unstructured":"Ang, Y.-S. et al. Disease model of GATA4 mutation reveals transcription factor cooperativity in human cardiogenesis. Cell 167, 1734\u20131749.e22 (2016).","journal-title":"Cell"},{"key":"59244_CR11","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.cell.2012.08.018","volume":"151","author":"CR Baker","year":"2012","unstructured":"Baker, C. R., Booth, L. N., Sorrells, T. R. & Johnson, A. D. Protein modularity, cooperative binding, and hybrid regulatory states underlie transcriptional network diversification. Cell 151, 80\u201395 (2012).","journal-title":"Cell"},{"key":"59244_CR12","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1126\/science.aax5217","volume":"367","author":"CS Britton","year":"2020","unstructured":"Britton, C. S., Sorrells, T. R. & Johnson, A. D. Protein-coding changes preceded cis-regulatory gains in a newly evolved transcription circuit. Science 367, 96\u2013100 (2020).","journal-title":"Science"},{"key":"59244_CR13","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1038\/sj.embor.7400679","volume":"7","author":"A Traven","year":"2006","unstructured":"Traven, A., Jelicic, B. & Sopta, M. Yeast Gal4: a transcriptional paradigm revisited. EMBO Rep. 7, 496\u2013499 (2006).","journal-title":"EMBO Rep."},{"key":"59244_CR14","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1534\/genetics.109.101063","volume":"182","author":"CL Kerwin","year":"2009","unstructured":"Kerwin, C. L. & Wykoff, D. D. Candida glabrata PHO4 is necessary and sufficient for Pho2-independent transcription of phosphate starvation genes. Genetics 182, 471\u2013479 (2009).","journal-title":"Genetics"},{"key":"59244_CR15","doi-asserted-by":"publisher","first-page":"e25157","DOI":"10.7554\/eLife.25157","volume":"6","author":"BZ He","year":"2017","unstructured":"He, B. Z., Zhou, X. & O\u2019Shea, E. K. Evolution of reduced co-activator dependence led to target expansion of a starvation response pathway. eLife 6, e25157 (2017).","journal-title":"eLife"},{"key":"59244_CR16","doi-asserted-by":"publisher","first-page":"2629","DOI":"10.1128\/MCB.18.5.2629","volume":"18","author":"S Barbaric","year":"1998","unstructured":"Barbaric, S., M\u00fcnsterk\u00f6tter, M., Goding, C. & H\u00f6rz, W. Cooperative Pho2-Pho4 interactions at the PHO5 promoter are critical for binding of Pho4 to UASp1 and for efficient transactivation by Pho4 at UASp2. Mol. Cell. Biol. 18, 2629\u20132639 (1998).","journal-title":"Mol. Cell. Biol."},{"key":"59244_CR17","doi-asserted-by":"publisher","first-page":"2597","DOI":"10.1038\/sj.emboj.7600230","volume":"23","author":"A Nourani","year":"2004","unstructured":"Nourani, A., Utley, R. T., Allard, S. & C\u00f4t\u00e9, J. Recruitment of the NuA4 complex poises the PHO5 promoter for chromatin remodeling and activation. EMBO J. 23, 2597\u20132607 (2004).","journal-title":"EMBO J."},{"key":"59244_CR18","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1093\/oxfordjournals.jbchem.a021713","volume":"121","author":"JP Magbanua","year":"1997","unstructured":"Magbanua, J. P., Ogawa, N., Harashima, S. & Oshima, Y. The transcriptional activators of the PHO regulon, Pho4p and Pho2p, interact directly with each other and with components of the basal transcription machinery in Saccharomyces cerevisiae. J. Biochem. 121, 1182\u20131189 (1997).","journal-title":"J. Biochem."},{"key":"59244_CR19","first-page":"358","volume":"251","author":"D Shao","year":"1996","unstructured":"Shao, D., Creasy, C. L. & Bergman, L. W. Interaction of Saccharomyces cerevisiae Pho2 with Pho4 increases the accessibility of the activation domain of Pho4. Mol. Gen. Genet. 251, 358\u2013364 (1996).","journal-title":"Mol. Gen. Genet."},{"key":"59244_CR20","doi-asserted-by":"publisher","first-page":"2192","DOI":"10.1002\/j.1460-2075.1994.tb06496.x","volume":"13","author":"PS Jayaraman","year":"1994","unstructured":"Jayaraman, P. S., Hirst, K. & Goding, C. R. The activation domain of a basic helix-loop-helix protein is masked by repressor interaction with domains distinct from that required for transcription regulation. EMBO J. 13, 2192\u20132199 (1994).","journal-title":"EMBO J."},{"key":"59244_CR21","first-page":"2224","volume":"10","author":"N Ogawa","year":"1990","unstructured":"Ogawa, N. & Oshima, Y. Functional domains of a positive regulatory protein, PHO4, for transcriptional control of the phosphatase regulon in Saccharomyces cerevisiae. Mol. Cell. Biol. 10, 2224\u20132236 (1990).","journal-title":"Mol. Cell. Biol."},{"key":"59244_CR22","doi-asserted-by":"publisher","first-page":"5818","DOI":"10.1128\/MCB.18.10.5818","volume":"18","author":"PC McAndrew","year":"1998","unstructured":"McAndrew, P. C., Svaren, J., Martin, S. R., H\u00f6rz, W. & Goding, C. R. Requirements for chromatin modulation and transcription activation by the Pho4 acidic activation domain. Mol. Cell. Biol. 18, 5818\u20135827 (1998).","journal-title":"Mol. Cell. Biol."},{"key":"59244_CR23","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1126\/science.284.5416.977","volume":"284","author":"A Komeili","year":"1999","unstructured":"Komeili, A. & O\u2019Shea, E. K. Roles of phosphorylation sites in regulating activity of the transcription factor Pho4. Science 284, 977\u2013980 (1999).","journal-title":"Science"},{"key":"59244_CR24","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1126\/science.271.5246.209","volume":"271","author":"EM O\u2019Neill","year":"1996","unstructured":"O\u2019Neill, E. M., Kaffman, A., Jolly, E. R. & O\u2019Shea, E. K. Regulation of PHO4 nuclear localization by the PHO80-PHO85 cyclin-CDK complex. Science 271, 209\u2013212 (1996).","journal-title":"Science"},{"key":"59244_CR25","doi-asserted-by":"publisher","first-page":"5410","DOI":"10.1002\/j.1460-2075.1994.tb06876.x","volume":"13","author":"K Hirst","year":"1994","unstructured":"Hirst, K., Fisher, F., McAndrew, P. C. & Goding, C. R. The transcription factor, the Cdk, its cyclin and their regulator: directing the transcriptional response to a nutritional signal. EMBO J. 13, 5410\u20135420 (1994).","journal-title":"EMBO J."},{"key":"59244_CR26","doi-asserted-by":"publisher","first-page":"4689","DOI":"10.1093\/emboj\/16.15.4689","volume":"16","author":"T Shimizu","year":"1997","unstructured":"Shimizu, T. et al. Crystal structure of PHO4 bHLH domain\u2013DNA complex: flanking base recognition. EMBO J. 16, 4689\u20134697 (1997).","journal-title":"EMBO J."},{"key":"59244_CR27","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1126\/science.8108735","volume":"263","author":"A Kaffman","year":"1994","unstructured":"Kaffman, A., Herskowitz, I., Tjian, R. & O\u2019Shea, E. K. Phosphorylation of the transcription factor PHO4 by a cyclin-CDK complex, PHO80-PHO85. Science 263, 1153\u20131156 (1994).","journal-title":"Science"},{"key":"59244_CR28","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.fgb.2018.04.004","volume":"115","author":"AL Gomes-Vieira","year":"2018","unstructured":"Gomes-Vieira, A. L. et al. Evolutionary conservation of a core fungal phosphate homeostasis pathway coupled to development in Blastocladiella emersonii. Fungal Genet. Biol. 115, 20\u201332 (2018).","journal-title":"Fungal Genet. Biol."},{"key":"59244_CR29","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1016\/j.celrep.2013.03.014","volume":"3","author":"R Gord\u00e2n","year":"2013","unstructured":"Gord\u00e2n, R. et al. Genomic regions flanking E-box binding sites influence DNA binding specificity of bHLH transcription factors through DNA shape. Cell Rep. 3, 1093\u20131104 (2013).","journal-title":"Cell Rep."},{"key":"59244_CR30","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.68068","volume":"10","author":"AL Sanborn","year":"2021","unstructured":"Sanborn, A. L. et al. Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator. eLife 10, e68068 (2021).","journal-title":"eLife"},{"key":"59244_CR31","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1016\/j.ygeno.2007.02.003","volume":"89","author":"S Piskacek","year":"2007","unstructured":"Piskacek, S. et al. Nine-amino-acid transactivation domain: establishment and prediction utilities. Genomics 89, 756\u2013768 (2007).","journal-title":"Genomics"},{"key":"59244_CR32","doi-asserted-by":"publisher","first-page":"37612","DOI":"10.1074\/jbc.M206125200","volume":"277","author":"LT Bhoite","year":"2002","unstructured":"Bhoite, L. T. et al. Mutations in the Pho2 (Bas2) transcription factor that differentially affect activation with its partner proteins Bas1, Pho4, and Swi5. J. Biol. Chem. 277, 37612\u201337618 (2002).","journal-title":"J. Biol. Chem."},{"key":"59244_CR33","doi-asserted-by":"publisher","first-page":"e2212151120","DOI":"10.1073\/pnas.2212151120","volume":"120","author":"H Ming Yip","year":"2023","unstructured":"Ming Yip, H., Cheng, S., Olson, E. J., Crone, M. & Maerkl, S. J. Perfect adaptation achieved by transport limitations governs the inorganic phosphate response in S. cerevisiae. Proc. Natl. Acad. Sci. USA 120, e2212151120 (2023).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"59244_CR34","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1016\/j.molcel.2023.03.006","volume":"83","author":"BT Donovan","year":"2023","unstructured":"Donovan, B. T. et al. Basic helix-loop-helix pioneer factors interact with the histone octamer to invade nucleosomes and generate nucleosome-depleted regions. Mol. Cell 83, 1251\u20131263.e6 (2023).","journal-title":"Mol. Cell"},{"key":"59244_CR35","doi-asserted-by":"publisher","first-page":"6873","DOI":"10.1021\/bi0602718","volume":"45","author":"J Liu","year":"2006","unstructured":"Liu, J. et al. Intrinsic disorder in transcription factors. Biochemistry 45, 6873\u20136888 (2006).","journal-title":"Biochemistry"},{"key":"59244_CR36","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/nature10595","volume":"480","author":"VJ Lynch","year":"2011","unstructured":"Lynch, V. J., May, G. & Wagner, G. P. Regulatory evolution through divergence of a phosphoswitch in the transcription factor CEBPB. Nature 480, 383\u2013386 (2011).","journal-title":"Nature"},{"key":"59244_CR37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009629","volume":"17","author":"IS Hsu","year":"2021","unstructured":"Hsu, I. S. et al. A functionally divergent intrinsically disordered region underlying the conservation of stochastic signaling. PLOS Genet. 17, e1009629 (2021).","journal-title":"PLOS Genet."},{"key":"59244_CR38","doi-asserted-by":"publisher","first-page":"E11302","DOI":"10.1073\/pnas.1814051115","volume":"115","author":"AS Krois","year":"2018","unstructured":"Krois, A. S., Dyson, H. J. & Wright, P. E. Long-range regulation of p53 DNA binding by its intrinsically disordered N-terminal transactivation domain. Proc. Natl Acad. Sci. 115, E11302\u2013E11310 (2018).","journal-title":"Proc. Natl Acad. Sci."},{"key":"59244_CR39","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.05.032","author":"S Brodsky","year":"2020","unstructured":"Brodsky, S. et al. Intrinsically disordered regions direct transcription factor in vivo binding specificity. Mol. Cell https:\/\/doi.org\/10.1016\/j.molcel.2020.05.032 (2020).","journal-title":"Mol. Cell"},{"key":"59244_CR40","doi-asserted-by":"crossref","unstructured":"Ferrie, J. J., Karr, J. P., Tjian, R. & Darzacq, X. \u201cStructure\u201d-function relationships in eukaryotic transcription factors: the role of intrinsically disordered regions in gene regulation. Mol. Cell 82, 3970\u20133984 (2022).","DOI":"10.1016\/j.molcel.2022.09.021"},{"key":"59244_CR41","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.12.004","author":"JJ Ferrie","year":"2023","unstructured":"Ferrie, J. J. et al. p300 is an obligate integrator of combinatorial transcription factor inputs. Mol. Cell https:\/\/doi.org\/10.1016\/j.molcel.2023.12.004 (2023). S1097-2765(23)01023\u20137.","journal-title":"Mol. Cell"},{"key":"59244_CR42","doi-asserted-by":"publisher","unstructured":"Mindel, V. et al. Intrinsically disordered regions of the Msn2 transcription factor encode multiple functions using interwoven sequence grammars. Nucleic Acids Res. gkad1191. https:\/\/doi.org\/10.1093\/nar\/gkad1191 (2023).","DOI":"10.1093\/nar\/gkad1191"},{"key":"59244_CR43","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1016\/j.molcel.2023.11.020","volume":"84","author":"D Ji","year":"2024","unstructured":"Ji, D. et al. FOXA1 forms biomolecular condensates that unpack condensed chromatin to function as a pioneer factor. Mol. Cell 84, 244\u2013260.e7 (2024).","journal-title":"Mol. Cell"},{"key":"59244_CR44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2016239118","volume":"118","author":"A Rives","year":"2021","unstructured":"Rives, A. et al. Biological structure and function emerge from scaling unsupervised learning to 250 million protein sequences. Proc. Natl. Acad. Sci. USA 118, e2016239118 (2021).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"59244_CR45","doi-asserted-by":"publisher","first-page":"e38","DOI":"10.1371\/journal.pbio.0060038","volume":"6","author":"BB Tuch","year":"2008","unstructured":"Tuch, B. B., Galgoczy, D. J., Hernday, A. D., Li, H. & Johnson, A. D. The evolution of combinatorial gene regulation in fungi. PLoS Biol. 6, e38 (2008).","journal-title":"PLoS Biol."},{"key":"59244_CR46","doi-asserted-by":"publisher","first-page":"5505","DOI":"10.1073\/pnas.0911905107","volume":"107","author":"I Wapinski","year":"2010","unstructured":"Wapinski, I. et al. Gene duplication and the evolution of ribosomal protein gene regulation in yeast. Proc. Natl. Acad. Sci. USA 107, 5505\u20135510 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"59244_CR47","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/nature05099","volume":"443","author":"AE Tsong","year":"2006","unstructured":"Tsong, A. E., Tuch, B. B., Li, H. & Johnson, A. D. Evolution of alternative transcriptional circuits with identical logic. Nature 443, 415\u2013420 (2006).","journal-title":"Nature"},{"key":"59244_CR48","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1101\/sqb.2015.80.027557","volume":"80","author":"I Nocedal","year":"2015","unstructured":"Nocedal, I. & Johnson, A. D. How transcription networks evolve and produce biological novelty. Cold Spring Harb. Symp. Quant. Biol. 80, 265\u2013274 (2015).","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"59244_CR49","doi-asserted-by":"publisher","first-page":"2067","DOI":"10.1172\/JCI31988","volume":"117","author":"DW Sherbenou","year":"2007","unstructured":"Sherbenou, D. W. & Druker, B. J. Applying the discovery of the Philadelphia chromosome. J. Clin. Investig. 117, 2067\u20132074 (2007).","journal-title":"J. Clin. Investig."},{"key":"59244_CR50","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1101\/gr.2821705","volume":"15","author":"CB Do","year":"2005","unstructured":"Do, C. B., Mahabhashyam, M. S. P., Brudno, M. & Batzoglou, S. ProbCons: probabilistic consistency-based multiple sequence alignment. Genome Res. 15, 330\u2013340 (2005).","journal-title":"Genome Res."},{"key":"59244_CR51","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1093\/bioinformatics\/btp033","volume":"25","author":"AM Waterhouse","year":"2009","unstructured":"Waterhouse, A. M., Procter, J. B., Martin, D. M. A., Clamp, M. & Barton, G. J. Jalview Version 2-a multiple sequence alignment editor and analysis workbench. Bioinformatics 25, 1189\u20131191 (2009).","journal-title":"Bioinformatics"},{"key":"59244_CR52","doi-asserted-by":"publisher","first-page":"1939","DOI":"10.1093\/bioinformatics\/bty045","volume":"34","author":"PV Troshin","year":"2018","unstructured":"Troshin, P. V. et al. JABAWS 2.2 distributed web services for Bioinformatics: protein disorder, conservation and RNA secondary structure. Bioinformatics 34, 1939\u20131940 (2018).","journal-title":"Bioinformatics"},{"key":"59244_CR53","doi-asserted-by":"publisher","first-page":"W402","DOI":"10.1093\/nar\/gkz297","volume":"47","author":"DWA Buchan","year":"2019","unstructured":"Buchan, D. W. A. & Jones, D. T. The PSIPRED Protein Analysis Workbench: 20 years on. Nucleic Acids Res. 47, W402\u2013W407 (2019).","journal-title":"Nucleic Acids Res."},{"key":"59244_CR54","doi-asserted-by":"publisher","unstructured":"Thomas-Chollier, M. et al. RSAT peak-motifs: motif analysis in full-size ChIP-seq datasets. Nucleic Acids Res. gkr1104. https:\/\/doi.org\/10.1093\/nar\/gkr1104 (2011).","DOI":"10.1093\/nar\/gkr1104"},{"key":"59244_CR55","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1101\/gr.275145.120","volume":"31","author":"Y Zhang","year":"2021","unstructured":"Zhang, Y., Ho, T. D., Buchler, N. E. & Gord\u00e2n, R. Competition for DNA binding between paralogous transcription factors determines their genomic occupancy and regulatory functions. Genome Res. 31, 1216\u20131229 (2021).","journal-title":"Genome Res."},{"key":"59244_CR56","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/nprot.2008.195","volume":"4","author":"MF Berger","year":"2009","unstructured":"Berger, M. F. & Bulyk, M. L. Universal protein-binding microarrays for the comprehensive characterization of the DNA-binding specificities of transcription factors. Nat. Protoc. 4, 393\u2013411 (2009).","journal-title":"Nat. Protoc."},{"key":"59244_CR57","doi-asserted-by":"crossref","unstructured":"Berger, M. F. & Bulyk, M. L. Protein binding microarrays (PBMs) for rapid, high-throughput characterization of the sequence specificities of DNA binding proteins. in Gene Mapping, Discovery, and Expression Vol. 338, 245\u2013260 (Humana Press, 2006).","DOI":"10.1385\/1-59745-097-9:245"},{"key":"59244_CR58","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1126\/science.1131007","volume":"315","author":"SJ Maerkl","year":"2007","unstructured":"Maerkl, S. J. & Quake, S. R. A systems approach to measuring the binding energy landscapes of transcription factors. Science 315, 233\u2013237 (2007).","journal-title":"Science"},{"key":"59244_CR59","doi-asserted-by":"publisher","unstructured":"Weeramange, C. J., Fairlamb, M. S., Singh, D., Fenton, A. W. & Swint\u2010Kruse, L. The strengths and limitations of using biolayer interferometry to monitor equilibrium titrations of biomolecules. Protein Sci. pro.3827. https:\/\/doi.org\/10.1002\/pro.3827 (2020).","DOI":"10.1002\/pro.3827"},{"key":"59244_CR60","doi-asserted-by":"publisher","unstructured":"Anand, R., Memisoglu, G. & Haber, J. Cas9-mediated gene editing in Saccharomyces cerevisiae. Protocol Exchange. https:\/\/doi.org\/10.1038\/protex.2017.021a (2017).","DOI":"10.1038\/protex.2017.021a"},{"key":"59244_CR61","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/nprot.2007.13","volume":"2","author":"RD Gietz","year":"2007","unstructured":"Gietz, R. D. & Schiestl, R. H. High-efficiency yeast transformation using the LiAc\/SS carrier DNA\/PEG method. Nat. Protoc. 2, 31\u201334 (2007).","journal-title":"Nat. Protoc."},{"key":"59244_CR62","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1038\/nature06867","volume":"453","author":"FH Lam","year":"2008","unstructured":"Lam, F. H., Steger, D. J. & O\u2019Shea, E. K. Chromatin decouples promoter threshold from dynamic range. Nature 453, 246\u2013250 (2008).","journal-title":"Nature"},{"key":"59244_CR63","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1093\/genetics\/144.4.1425","volume":"144","author":"P James","year":"1996","unstructured":"James, P., Halladay, J. & Craig, E. A. Genomic libraries and a host strain designed for highly efficient two-hybrid selection in yeast. Genetics 144, 1425\u20131436 (1996).","journal-title":"Genetics"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-59244-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-59244-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-59244-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T14:02:34Z","timestamp":1750255354000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-59244-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,18]]},"references-count":63,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["59244"],"URL":"https:\/\/doi.org\/10.1038\/s41467-025-59244-w","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.04.20.590343","asserted-by":"object"}]},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,18]]},"assertion":[{"value":"28 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5340"}}