Cells have an amazing ability to process information, make decisions, and change their state in response to changing environments – all behaviors that bioengineers and synthetic biologists are trying to harness for a broad array of applications in health and sustainability. These behaviors are encoded in the DNA genome of the cell as genetic ‘programs’ that use the basic chemical processes of gene expression to synthesize cellular RNAs and proteins in specific patterns that determine cellular function. Thus our ability to control cellular behavior is directly connected to our ability to control and engineer gene expression, making this a central goal of bioengineering and synthetic biology. RNAs are emerging as a particularly attractive substrate for engineering gene expression and cell behavior since they are now known to control almost all aspects of gene expression. As with many biomolecules, RNA function is intimately related to its structure. Central questions in biology and bioengineering are then: How do RNAs fold inside cells?, and How can we engineer these folds to control gene expression? In this talk I will present our work at the interface of these two questions that is starting to uncover design principles for engineering RNAs that can be used in an array of applications, from metabolic engineering to new types of diagnostics. I will start by presenting our work on engineering RNA molecular switches that control the basic process of RNA synthesis, or transcription. The desire to uncover design principles for engineering these RNAs motivates our development of in-cell SHAPE-Seq, a technology that couples chemical probing with next-generation sequencing that simultaneously characterizes the structures and functions of RNA regulatory molecules as they exist inside cells. I will describe how this technique is uncovered principles of the RNA structure/function relationship that has allowed us to engineer an RNA regulatory mechanism not found in nature. This new mechanism, called Small Transcription Activating RNAs, or STARs, allows new types of RNA-based genetic circuits and logics to be built that are opening up new avenues for using RNAs to control cellular systems. I will conclude with thoughts about how our work is leading us to ask deeper scientific questions about the fundamental processes of RNA folding and function, and how the answers to these questions will continue to develop a discipline of RNA engineering.

Controlling cells through RNA Folding: Towards design principles for RNA engineering

251st National Meeting (2016)

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