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Preferences in a Trait Decision Determined by Transcription Factor Variants

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Preferences in a Trait Decision Determined by Transcription Factor Variants Preferences in a trait decision determined by transcription factor variants Michael W. Dorritya,b, Josh T. Cuperusa,c, Jolie A. Carlislea, Stanley Fieldsa,c,d,1, and Christine Queitscha,1 aDepartment of Genome Sciences, University of Washington, Seattle, WA 98195; bDepartment of Biology, University of Washington, Seattle, WA 98195; cHoward Hughes Medical Institute, University of Washington, Seattle, WA 98195; and dDepartment of Medicine, University of Washington, Seattle, WA 98195 Contributed by Stanley Fields, June 27, 2018 (sent for review April 9, 2018; reviewed by Leah E. Cowen and Andrew W. Murray) Few mechanisms are known that explain how transcription factors mating, Ste12 can bind at pheromone-responsive genes as a can adjust phenotypic outputs to accommodate differing environ- homodimer or with the cofactors Mcm1 or Matα1 (10–13). The ments. In Saccharomyces cerevisiae, the decision to mate or invade consensus DNA-binding site of Ste12 is TGAAAC, known as the relies on environmental cues that converge on a shared transcription pheromone response element (PRE) (11). For invasion, Ste12 factor, Ste12. Specificity toward invasion occurs via Ste12 binding and its cofactor Tec1 are both required to activate genes that me- cooperatively with the cofactor Tec1. Here, we determine the range diate filamentation (8, 14, 15). Some of these genes contain a of phenotypic outputs (mating vs. invasion) of thousands of DNA- Ste12 binding site near a Tec1 consensus sequence of GAATGT, an binding domain variants in Ste12 to understand how preference for organization for heterodimeric binding known as a filamentation invasion may arise. We find that single amino acid changes in the response element (FRE). An alternative model, however, posits that DNA-binding domain can shift the preference of yeast toward either expression of invasion genes is driven by a complex of Ste12 and mating or invasion. These mutations define two distinct regions of Tec1, acting solely through Tec1 binding sites (15). An environmental this domain, suggesting alternative modes of DNA binding for each component of trait specificity has been shown in fungi that are animal trait. We characterize the DNA-binding specificity of wild-type pathogens; upon recognition of host body temperature (37 °C) (6), Ste12 to identify a strong preference for spacing and orientation Cryptococcus neoformans has decreased mating efficiency but in- of both homodimeric and heterodimeric sites. Ste12 mutants that creased ability to invade (16). Although trait preference in S. cerevisiae promote hyperinvasion in a Tec1-independent manner fail to bind cooperative sites with Tec1 and bind to unusual dimeric Ste12 sites depends on Ste12, the role of this protein in regulating mating and composed of one near-perfect and one highly degenerate site. We invasion in response to increased temperature is unknown. propose a model in which Ste12 alone may have evolved to activate Because the highly conserved Ste12 DNA-binding domain invasion genes, which could explain how preference for invasion ultimately enacts the choice between mating and invasion, here arose in the many fungal pathogens that lack Tec1. we sought to precisely define its DNA-binding specificity and ex- amine the consequences of mutations and increased temperature yeast | transcription factor | fungal mating | fungal invasion | on the balance of these traits. We reveal distinct organizational evolutionary trade-off preferences for both homodimeric binding sites and cooperative GENETICS heterodimeric binding sites with Tec1. Furthermore, single amino ranscription factors interact with DNA, with cofactors, and acid changes suffice to shift the preference of yeast cells toward Twith signaling proteins to allow cells to respond to changes in one or the other trait; they also suffice to confer dependence on their environment. Despite the requirement to manage these multiple levels of regulation, most eukaryotic transcription factors Significance possess a single DNA-binding domain. Distinct responses must therefore be mediated by diversity in cofactors, organizations of Transcription factors have been intensively examined to de- binding sites, and conformational changes in the transcription cipher how they regulate cellular decisions, but there are few in- factor itself. For example, human GCM1 gains a novel recognition depth studies of these factors across traits, environments, and sequence when paired with the ETS family factor ELK1 (1); genetic backgrounds. Here, we analyze the Saccharomyces cer- auxin-responsive transcription factors regulate expression differ- evisiae Ste12 protein, a transcription factor essential for both entially depending on the arrangement of their binding sites (2); mating and invasion in many fungal species. Generating thou- and the heat-shock factor Hsf1 senses increased temperature by sands of variants in the Ste12 DNA-binding domain, we scored changing its conformation, which allows it to bind a unique rec- each variant for its activity in promoting both mating and in- ognition sequence (3). vasion. We found altered DNA-binding patterns of exceptional We sought to investigate the features of a single transcription variants that result in yeast that lose their mating efficiency, but factor that uses distinct cofactors, binding sites, and environmental gain increased competence in invasion. This surprising mallea- inputs to mediate a cellular decision. The Ste12 protein of the bility in transcription factor function has implications for un- yeast Saccharomyces cerevisiae governs the choice of mating or derstanding the evolution of pathogenicity in fungi. invasion. Each of these traits contributes to cellular fitness: mating Author contributions: M.W.D., J.T.C., S.F., and C.Q. designed research; M.W.D. and J.A.C. of haploid yeast cells is required for meiotic recombination, and performed research; M.W.D. contributed new reagents/analytic tools; M.W.D. analyzed invasion allows a cell to forage for nutrients or to penetrate tis- data; and M.W.D., S.F., and C.Q. wrote the paper. sues, a characteristic of pathogenic fungi. Mating is initiated by Reviewers: L.E.C., University of Toronto; and A.W.M., Harvard University. binding of the appropriate pheromone, which activates an evolu- The authors declare no conflict of interest. tionarily conserved G protein-coupled mitogen-activated protein Published under the PNAS license. kinase (MAPK) pathway (4, 5) (Fig. 1A). In contrast, invasion is Data deposition: The high-throughput sequence reads reported in this paper have been initiated in response to increased temperature and limited nutri- deposited in the National Center for Biotechnology Information Sequence Read Archive, ent availability (6–8). The shared protein kinase Ste11, a client of https://www.ncbi.nlm.nih.gov/sra (accession nos. SRR5408956–SRR5408965). the chaperone Hsp90 (9), likely contributes to the environmental 1To whom correspondence may be addressed. Email: [email protected] or [email protected]. sensitivity of both traits. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. The two pathways converge on Ste12, which interacts differ- 1073/pnas.1805882115/-/DCSupplemental. entially with cofactors to activate either mating or invasion. For Published online August 1, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1805882115 PNAS | vol. 115 | no. 34 | E7997–E8006 Downloaded by guest on September 25, 2021 AD E F B C Fig. 1. Conservation of Ste12 and Tec1 and their DNA-binding sites. (A) The yeast mating and invasion pathways contain shared signaling components, and both depend on Ste12 for activation of distinct regulatory programs. (B) S. cerevisiae Ste12 protein has a nonconserved transcriptional activation domain, as well as a highly conserved DNA-binding domain. The secondary structure of this domain is predicted to contain a pattern of α-helices (gray boxes) interspersed with β-sheets (blue arrows) that are conserved among all fungal species. The region of the DNA-binding domain chosen for mutagenesis is shaded in orange. (C) A logo plot of the conserved portion of the DNA-binding domain of Ste12 generated from 1,229 fungal species. (D) A phylogeny of fungal species selected for those with functionally tested STE12 genes (except for the basal fungi Rhizophagus irregularis and Rozella allomycis, shown as outgroups). Pathogenic species are indicated with circles and colored according to plant (green) or animal (red) hosts. All fungal species were queried for the presence of a STE12 (blue) or TEC1 (orange) gene, and filled squares indicate presence of either gene; numbers inside boxes indicate species with multiple gene copies. Results for all species are shown below each gene’s column. (E) Proportional bar chart showing the number of S. cerevisiae genes that contain Ste12 sites (blue), Tec1 and Ste12 sites (yellow), and adjacent sites fewer than 24 bases from each other (green). (F) Histogram showing frequencies of spacing between all Ste12 and Tec1 binding sites in the S. cerevisiae genome. Negative values indicate that the Tec1 site is 5′ of the Ste12 site, and positive values the converse. the chaperone Hsp90 and responsiveness to higher temperature. Cooperative binding at adjacent (within 24 bp) Ste12 and Tec1 Some hyperinvasive separation-of-function mutations are in- binding sites (FREs) has been demonstrated in vivo and in vitro dependent of the cofactor Tec1, thought to be essential for in- (18), although most invasion genes do not contain FREs (15). For vasion.
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