ABSTRACT

Living organisms have to adjust to changes in their environment in order to optimize their use of resources, minimize stress and maintain stability. This proposal aims to uncover the basic principles that direct how organisms tailor their physiological responses to environmental changes. Understanding why certain responses occur requires a precise map showing which genes are regulated in a given response and how they are coordinated. Using prior NSF ABI support, the Baliga Laboratory at the Institute for Systems Biology developed an approach to create precise maps of gene regulation for any microbial species. Using this approach, they mapped gene regulation in a set of important organisms including uranium-reducing Desulfovibrio vulgaris, lipid-accumulating Chlamydomonas reinhardtii, yeast, diatoms, and Mycobacterium tuberculosis. The next goal is to see how well the maps work as tools to predict the results when manipulating complex behaviors. Effective tools have wide-ranging implications for biotechnology, agriculture and medicine. Initially, new algorithms and software will be developed to further refine the gene regulation maps and identify factors affecting gene regulation during environmental changes. The focus will be understanding how organisms switch on or off specific behaviors in response to environmental cues. The work will be performed in two organisms - E. coli, a well-known, widely studied bacterium, and Halobacterium salinarum, an extremophile that thrives in high salt environments; it will be readily applicable to all sequenced microorganisms that are of significant industrial, agricultural, and medical importance. Part of the project is to develop and disseminate new high school curriculum to introduce the importance of computational modeling in solving real world problems such as food scarcity and climate change. Diverse populations of students and teachers from a variety of backgrounds, including those currently underrepresented in science, technology, engineering and math (STEM), will receive training and sustained support as they learn this interdisciplinary science. This curriculum and training is part of a program called Systems Education Experiences (SEE) that reaches thousands of students and teachers each month. SEE works toward cultivating systems thinkers who can tackle problems, contribute to a STEM-literate citizenry, and help build a more diverse population of STEM professionals.

The primary objective of this project is to develop a framework to elucidate and predictably manipulate the gene regulatory program of any microbe. In previous ABI-funded research, the Baliga lab developed a systems approach to reverse engineer the environment and gene regulatory influence network v2.0 (EGRIN 2.0) model directly from a compendium of transcriptome profiles. The EGRIN 2.0 model elucidates mechanisms for environment-specific transcriptional regulation of all genes with unprecedented nucleotide-level resolution, at canonical promoter locations and even within coding sequences and inside operons. Here, an approach will be developed to elucidate transcription factor interactions within EGRIN 2.0 and characterize how the topology of these interactions (i.e., 'network motifs') generates genome-wide, temporally coordinated transcriptional responses. These studies will be performed in the context of understanding how two phylogenetically distant organisms --Escherichia coli (a bacterium) and Halobacterium salinarum (an archaeaon)-- use distinct regulators to mediate physiologically different yet phenotypically similar transitions from aerobic growth to anaerobic quiescence. First, an approach will be developed to precisely map conditional binding of transcription factors to sequence elements within promoters of all genes in the genome (EGRIN 3.0). Next, EGRIN 3.0 will be used to identify, characterize, and manipulate topologies of transcription factor interactions (i.e., network motifs) to predictably alter oxygen (O2)-responsive state transitions in H. salinarum and E. coli. In addition to developing a generalized framework for manipulating a microbial gene regulatory program within any organism, the activities will test the hypothesis that similar environmental forcing drives convergent evolution of topologically similar network motifs in phylogenetically distant organisms. The high-level thinking and process used by this interdisciplinary group will be translated into curriculum and training experiences in the form of real-word cases studies for high school teachers and students. One of the goals will be for students to use experimentation and modeling to better understand the influence of environmental parameters (such as oxygen, nitrates, pH, light, etc.) on productivity and stability of food systems, such as aquaponic systems. Students, teachers, and STEM professionals will work together to iteratively develop and test curriculum and experiences through a modified Dick and Carey Instructional Design model. All curricula will be integrated with published national education standards. All needed technology, software, lesson plans and learning aides will be provided to teachers and students through multiple online sources, resource centers, and in-person and online trainings. For further information about this project and its products, visit the Baliga Laboratory's website at http://baliga.systemsbiology.net and http://see.systemsbiology.net.

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