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Article Epistatic Interactions in the Arabinose Cis-Regulatory Element Epistatic Interactions in the Arabinose Cis-Regulatory Element Mato Lagator,*,1 Claudia Igler,1 Anaısa B. Moreno,1 Calin C. Guet,1 and Jonathan P. Bollback1 1IST Austria, Klosterneuburg, Austria *Corresponding author: E-mail: [email protected]. Associate editor: Patricia Wittkopp Abstract Changes in gene expression are an important mode of evolution; however, the proximate mechanism of these changes is poorly understood. In particular, little is known about the effects of mutations within cis binding sites for transcription factors, or the nature of epistatic interactions between these mutations. Here, we tested the effects of single and double mutants in two cis binding sites involved in the transcriptional regulation of the Escherichia coli araBAD operon, a component of arabinose metabolism, using a synthetic system. This system decouples transcriptional control from any Downloaded from posttranslational effects on fitness, allowing a precise estimate of the effect of single and double mutations, and hence epistasis, on gene expression. We found that epistatic interactions between mutations in the araBAD cis-regulatory element are common, and that the predominant form of epistasis is negative. The magnitude of the interactions depended on whether the mutations are located in the same or in different operator sites. Importantly, these epistatic interactions were dependent on the presence of arabinose, a native inducer of the araBAD operon in vivo, with some http://mbe.oxfordjournals.org/ interactions changing in sign (e.g., from negative to positive) in its presence. This study thus reveals that mutations in even relatively simple cis-regulatory elements interact in complex ways such that selection on the level of gene expression in one environment might perturb regulation in the other environment in an unpredictable and uncorrelated manner. Key words: gene expression; gene regulation; epistasis; cis-regulatory elements. Introduction critical to understanding adaptation and the engineering of Changes in the cis regulation of gene expression have been synthetic promoters with specific properties (Kinkhabwala at Institute of Science and Technology Austria on May 25, 2016 proposed as a major source of evolutionary innovation (King and Guet 2008). That is, the phenotypes (gene expression and Wilson 1975; Wittkopp and Kalay 2012). For example, levels, in the case of CREs) of individuals containing multiple across insect species there has been increasing evidence for mutations are expected to correspond to those of the under- theessentialrolethatcis regulatory changes have in shaping lying single mutant phenotypes. Instead, however, the phe- body plan formation (Carroll 2000, 2008; Wittkopp and Kalay notypes might deviate from this expectation, resulting in 2012). Changes in the regulation of gene expression can occur positive epistasis if the mean double mutant expression is through mutations in the transcription factor coding se- greater than the expression level predicted from single mu- Article quence (transregulatory elements) and/or in cis-regulatory tants. If the double mutant expression is lower than predicted, elements (CREs), which contain the transcription factor and then mutations are considered to be in negative epistasis. If the RNA polymerase (RNAP) binding sites (Jacob and Monod the individual mutation causes an increase in the expression 1961). Mutations in CREs may be important targets of selec- but the double mutant containing that mutation leads to its tion (Stern and Orgogozo 2008), as it is hypothesized that, reduction (or vice versa), the mutation is deemed to be in sign compared with trans elements, mutations in CREs have a epistasis (Phillips 2008). Epistatic interactions between muta- wider range of effects, giving rise to a greater diversity of tionsinCREsdefinetherobustnessaswellastheevolvability phenotypes that could be selected upon (Wray 2007). of regulatory elements—not only how transcription levels can Previous studies have described distributions of mutational be modulated but also how new functional CREs could evolve effects for several prokaryotic CREs both in vitro (Maerkl and (Payne and Wagner 2014). Quake 2007, 2009; Geertz et al. 2012)andinvivo(Patwardhan The functional effects of epistatic interactions are complex et al. 2009; Kinney et al. 2010; Brewster et al. 2012; Sharon et al. and therefore poorly understood, as epistasis may be influ- 2012; Kosuri et al. 2013). As these studies predominantly fo- enced by many factors (Lehner 2011). Epistasis can depend on cused on characterizing general relationships between trans environmental factors, as has been demonstrated for muta- factors (TFs and RNAP) and their cis binding sites, the analysis tions in bacterial and bacteriophage proteins (You and Yin of interactions between individual cis mutations has been 2002; Hayden and Wagner 2012; Lalic and Elena 2012; Wang, limited (Kwasnieski et al. 2012), partly due to restrictions in Diaz Arenas, et al. 2012; de Vos et al. 2013; Flynn et al. 2013; the techniques used (Melnikov et al. 2012; Patwardhan et al. Caudle et al. 2014). As cellular responses to environmental 2012). Understanding the dependence of the effect of a mu- changes can be complex, understanding their effect on epis- tation on the genetic background in which it appears, a phe- tasis is inherently difficult. Some prokaryotic regulatory path- nomenon termed epistasis (Fisher 1918; Phillips 2008)is ways, however, offer a tractable system for understanding the ß The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Open Access Mol. Biol. Evol. 33(3):761–769 doi:10.1093/molbev/msv269 Advance Access publication November 20, 2015 761 Lagator et al. doi:10.1093/molbev/msv269 MBE environmental response, with predictable responses to single supplementary tables S1 and S2, Supplementary Material stimuli modulating gene expression (Browning and Busby online), which is not surprising as all mutated sites are fully 2004). One such regulatory pathway is that of the well-studied conserved within the Enterobacteriaceae family (supplemen- Escherichia coli arabinose operon araBAD (Helling and tary fig. S2c, Supplementary Material online). Surprisingly, Weinberg 1963; Schleif 2000)(fig. 1). This operon is activated three mutations increased expression in the presence of arab- in the presence of its substrate, the sugar arabinose, which inose (fig. 2a), in apparent contradiction to previous reports interacts with the transcription factor AraC. By synthetically that all possible mutations in tested sites decreased AraC associating the araBAD CRE with a fluorescence marker in- binding by at least 10-fold (Niland et al. 1996). We tested if stead of the native araBAD operon,wehavedecoupledthe this disparity arose from the fact that the construct was on a effects of mutations in CRE on expression from any potential low copy number plasmid rather than on the chromosome, downstream effects that might affect global expression (fig. but found no difference in the response of the two systems to 1c). This allows us to directly study the effects of mutations on arabinose (supplementary fig. S1, Supplementary Material CRE and their epistatic interactions, in the presence and ab- online). The observed results, however, are in accordance sence of a single, well-understood, and controlled environ- with the position weight matrix for AraC binding (supple- Downloaded from mental variable, arabinose. mentary fig. S2, Supplementary Material online) obtained Epistatic interactions can also depend on the physical loca- from RegulonDB (Salgado et al. 2013). As these sites are tion of mutations. For example, the type and magnitude of fully conserved, our result suggests that the optimal level of interactions can be different for pairs of mutations found araBAD expression, even in the presence of arabinose, is lower withinageneandthoseindifferentgenes(Szendro et al. than the maximum possible expression level. In the absence http://mbe.oxfordjournals.org/ 2013), or for mutations found in genes that interact and of arabinose, all tested mutations either significantly increased those that do not (Lalic and Elena 2012). We investigated if expression from araBAD CRE, leading to less tight repression, the differences in epistasis in CRE might depend on whether or left it unaffected (figs. 2b and 3b and supplementary table thosemutationsarefoundinthesameorindifferentopera- S2, Supplementary Material online). tors. Epistasis in a CRE could arise from the effects of mutations on transcription factor binding to its operator site. But it could Epistatic Interactions Are Environment Dependent also arise from an interaction between the effects of mutations We identified significant epistatic interactions, measured as and the constraints imposed by protein–protein interactions the deviation of the double mutant expression from the mul- at Institute of Science and Technology Austria on May 25, 2016 that stabilize transcription factor DNA binding, as could be tiplicative expectation of expression based on the corre- true for both AraC and the AraC–arabinose complex, which sponding single mutant effects, for exactly half (10 out of bind as dimers (Schleif 2003). Epistasis
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