Engineering autoregulation of the epitranscriptome to track and control stress responses

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Environmental stressors of biological systems are highly complex. It has been postulated that environmental stressors can result in RNA modifications in biological cells. The study of such modifications is known as epitranscriptomics. In this project, an interdisciplinary team of researchers, including graduate students and undergraduate students, are using epitranscriptomics to study how chemically induced changes in RNA molecules within biological cells could be used to record environmental stresses. The study makes use of computational tools, biochemical characterization, traditional genetics methods as well as tools in Next Generation Sequencing. These studies contribute to the general understanding of how cells sense, record and respond to their environments and are important for understanding how to design early warning systems for virus detection for example. The project provides research opportunities to students from low-income underrepresented communities through the “Raising Future Scientists” program at the University of Texas at Austin. Emphasis is given on promoting participation of undergraduate students as a way to encourage their interest in graduate programs in science and engineering. The project also contributes to the advancement of the public-school synthetic biology curriculum.This proposal uses the epitranscriptome as a mechanism to sense, record, and respond to the complexities of the environment. The goal is to utilize RNA modifications in new classes of modular devices that combine sensory RNA motifs, called “RNA Sensors,” with activating protein domains, or “Protein Actuators”, to enable engineered regulation of cellular responses. The research combines integrated systems approaches involving computational tools, molecular RNA-protein biochemical characterization strategies, traditional genetics methods, and novel, in vivo Next Generation Sequencing-based tools to accomplish three objectives: (i) establish the epitranscriptome as a sensory module in bacteria, (ii) rationally re-engineer 8-OG recognition proteins as actuating modules, and (iii) couple sensing and actuation of the epitranscriptome with CRISPR-systems for signaling, memory, and stress response control capabilities. Results from this research are broadly applicable in the field of synthetic biology and could be used for understanding specific environmental exposures for risk assessment and interventions.This proposal is jointly funded by the Systems and Synthetic Biology program in the Division of Molecular and Cellular Biosciences and the Cellular and Biochemical Engineering program in the Division of Chemical Bioengineering Environmental and Transport Systems.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.