Jeffrey A. Lewis
J. William Fulbright College of Arts & Sciences
All organisms must endure diverse environmental stresses during their lifetime. Our lab seeks to understand how microbes adapt and even thrive in the face of various environmental assaults. Microbial stress responses are remarkably complex, coordinating multiple levels of sensing, signal transduction, and global regulatory networks. Thus, stress research feeds into nearly all aspects of cell biology, with implications for human disease, microbial pathogenesis, and the evolution of regulatory networks.
Our group studies stress responses through the perspective of natural variation. Inarguably, model organisms have provided fundamental insights into basic biology. However, most of our knowledge derives from a small number of domesticated lines—we lack a detailed knowledge of the ecology and phenotypic diversity of different individuals within the same microbial species. With the advent of genomic technologies, we are now uniquely poised to perform comparative genomic studies on wild microbial strains. We use these powerful new approaches, as well as classical genetics and biochemistry, to identify stress regulatory pathways, non-coding RNAs, and genes with previously unknown functions.
Our lab studies how microbes sense and respond to various environmental assaults. We take advantage of natural variation between wild microbial isolates to understand how the environment and evolution shape the stress responses and physiology of microorganisms. We use a combination of genomic, genetic, and biochemical approaches to study the following areas:
Natural variation in yeast stress responses
Understanding how gene-environment interactions determine phenotype is a fundamental goal in genetics. For many traits, including several of clinical importance, this interplay is complex—multiple genes interact with environmental factors in a combinatorial manner. We use yeast stress responses as a model to study gene-environment interactions, gene regulatory divergence, and the genetics of complex traits. We have performed expression quantitative trait loci (eQTL) mapping of the yeast ethanol response, which is providing a wealth of insights into the genetic source of regulatory divergence between wild and laboratory yeast strains. We are currently using bulk-segregant analysis to identify connections between ethanol signaling and ethanol-mediated cross-protection against other stresses.
Role of post-translational protein modifications in response to stress
Recent evidence suggests that the function of stress-activated gene expression is not to survive the initial insult, but instead protects against an impending severe stress. Consistent will this idea, maximal gene expression changes can take over half an hour—far too long a timescale to provide acute protection from stress. In contrast, post-translational protein modifications (PTMs) happen on the order of seconds, allowing for rapid regulation in response to acute stress. In support of a role for PTMs in the immediate response to stress is the observation that numerous stress defense proteins have PTMs. How these PTMs affect stress defense remains mostly unknown. We are using biochemical, genetic, and molecular approaches to understand the physiological role of PTMs, namely acetylation, during the acute response to stress. We are also using quantitative genetics (QTL mapping) to explore the genetic basis of natural variation in PTMs in wild and laboratory yeast strains. These studies will shed light on potential stress-responsive regulators of PTMs.
Function of stress-regulated non-coding RNAs
Multiple studies have found that a much larger portion of the genome is transcribed than was originally thought. The vast majority of these novel transcripts do not code for proteins. The functions for most of these non-coding (nc) RNAs remain obscure, but many are hypothesized to play regulatory roles. We have identified hundreds of stress-regulated ncRNAs, as well as extensive natural variation in ncRNA expression across different strain backgrounds. We are employing eQTL mapping of ncRNAs to identify novel regulators of ncRNA expression, and to generate and test hypotheses for ncRNA function.
Insights into the domestication of yeast.
In collaboration with Dana Wohlbach at Dickinson College, we are performing laboratory evolution to understand the genomic changes that accompany domestication of yeast.
The response of yeast to extreme pressure and temperature.
In collaboration with Pradeep Kumar at the University of Arkansas, we are working to understand how yeast cells respond and evolve to both high hydrostatic pressures and temperatures, which appear to elicit partially overlapping responses.
Development of genetic tools for marine microbes.
In collaboration with Andy Alverson at the University of Arkansas, we have received funding from the Gordon and Betty Moore Foundation to develop a transformation system and new genetic tools for diatoms.
The impact of fracking on microbial communities.
In collaboration with Marlis Douglas and Michael Douglas, we are determining whether stream biofilm communities are sensitive to the chemical signatures of fracking.
Yeast and bacterial stress responses and physiology, comparative genomics, natural variation in yeast, microbial genetics and biochemistry
General Genetics, Biological Regulation and Subcellular Communication
Ph.D. University of Wisconsin, 2007
B.S. University of California, Santa Barbara, 2001
- Stuecker TN, Scholes AN, Lewis JA. 2017. Linkage mapping of yeast cross protection connects gene expression variation to a higher-order organismal trait. BioRxiv.
- Nguyen K, Marray S, Lewis JA, Kumar P. 2017. Morphology, cell division, and viability of Saccharomyces cerevisiae at high hydrostatic pressure. arXiv.
- Johnson WH, Douglas MR, Lewis JA, Stuecker TN, Carbonero FG, Austin BJ, Evans-White MA, Entrekin SA, Douglas ME. 2017. Do biofilm communities respond to the chemical signatures of fracking? A test involving streams in North-central Arkansas. BMC Microbiology. 17(1):29
- Lewis JA, Broman AT, Will J, Gasch AP. 2014. Genetic Architecture of Ethanol-Responsive Transcriptome Variation in Saccharomyces cerevisiae Strains. Genetics. 198(1):369-382 PMC4174948
- Wohlbach DJ, Rovinskiy N, Lewis JA, Sardi M, Schackwitz WS, Martin JA, Deshpande S, Daum CG, Lipzen A, Sato TK, Gasch AP. 2014. Comparative genomics of Saccharomyces cerevisiae natural isolates for bioenergy production. Genome Biol. Evol. 6(9):2557-2566 PMC4202335
- Gonçalves A, Ong I, Lewis JA, Costa VS. 2014. Towards using probabilities and logic to model regulatory networks. 2014 IEEE 27th International Symposium on Computer-Based Medical Systems: 239-242
- Gonçalves A, Ong I, Lewis JA, Costa VS. 2014. Discovering differentially expressed genes in yeast stress data. 2014 IEEE 27th International Symposium on Computer-Based Medical Systems: 537-538
- Lewis JA, Gasch AP. 2012. Natural variation in the yeast glucose-signaling network reveals a new role for the Mig3p transcription factor. G3 (Bethesda). 2(12):1607-1612 PMC3516482
- Gonçalves A, Ong I, Lewis JA, Costa VS. A ProbLog model for analyzing gene regulatory networks. 22nd International Conference on Inductive Logic Programming: 38-43
- Lewis JA, Elkon IM, McGee MA, Higbee AJ, Gasch AP. 2010. Exploiting natural variation in Saccharomyces cerevisiae to identify genes for increased ethanol resistance. Genetics. 186(4):1197-1205 PMC2998304
- Lewis JA, Stamper LW, Escalante-Semerena JC. 2009. Regulation of expression of the tricarballylate utilization operon (tcuABC) of Salmonella enterica. Res. Microbiol. 160(3):179-186 PMC2692759
- Lewis JA, Boyd JM, Downs DM, Escalante-Semerena JC. 2009. Involvement of the Cra global regulatory protein in the expression of the iscRSUA operon, revealed during studies of tricarballylate catabolism in Salmonella enterica J. Bacteriol. 191(7):2069-2076 PMC2655522
- Boyd JM, Lewis JA, Escalante-Semerena JC, Downs DM. 2008. Salmonella enterica requires ApbC function for growth on tricarballylate: Evidence of functional redundancy between ApbC and IscU J. Bacteriol. 190(13):4596-4602 PMC2446783
- Lewis JA, Escalante-Semerena JC. 2007. Tricarballylate catabolism in Salmonella enterica. The TcuB protein uses 4Fe-4S clusters and heme to transfer electrons from FADH2 in the tricarballylate dehydrogenase (TcuA) enzyme to electron acceptors in the cell membrane. Biochemistry 46(31):9107-9115
- Lewis JA, Escalante-Semerena JC. 2006. The FAD-dependent tricarballylate dehydrogenase (TcuA) enzyme of Salmonella enterica converts tricarballylate into cis-aconitate. J. Bacteriol. 188(15):5479-5486 PMC1540016
- Lewis JA, Horswill AR, Schwem BE, Escalante-Semerena JC. 2004. The Tricarballylate utilization (tcuRABC) genes of Salmonella enterica serovar Typhimurium LT2. J. Bacteriol. 186(6):1629-1637 PMC355976