Understanding RNA Folding and Function Through RNA Synthetic Biology

A major theme of our work is to use fundamental science to drive new principles to engineer RNAs. In addition to creating new tools for controlling cellular processes, this approach is a precise and powerful means of uncovering principles of how natural RNAs function. For example, we have long been interested in answering the question: If we understand nascent RNA-folding pathways, can we design synthetic trans-acting RNAs to interfere with these folding pathways to create new modes of RNA regulation? This question led to the creation of completely new synthetic-RNA regulatory mechanisms called Small Transcription Activating RNAs (STARs) that use designed RNA structures to activate transcription. This research has also led to new designs for antisense RNAs that repress translation in bacteria, as well as a new concept called Looped Antisense Oligos (LASOs), which we hope may improve the design of antisense RNAs in therapeutic applications. In addition to designing specific regulatory RNAs, we have shown that entire networks of synthetic RNAs can precisely define temporal patterns of gene expression, operate faster than some protein networks, and can be used tocreate new modular RNA “logic gates” that act as molecular computers to process cellular information. In ongoing work we are using synthetic RNAs within a new concept of feedback regulation of metabolic pathways that allows new efficient strategies for bioproduction of important drugs and compounds. Building on our recent breakthroughs in understanding the principles of cotranscriptional RNA folding, we are now interested in asking: Can we computationally design entire RNA folding pathways to generate RNAs that dynamically control cellular processes? We are particularly interested in designing dynamic RNA systems to control transcription, as they can serve as powerful model systems to link folding pathways directly to function and are useful tools to control gene expression. 

Featured Publications: 
1. Dynamic control of pathway expression with riboregulated switchable feedback promoters.
C.J. Glasscock, J.T. Lazar, B.W. Biggs, J.H. Arnold, M-K Kang, D. Tullman-Ercek, K.E.J. Tyo, J.B. Lucks*. (2019).
Links: BioRxiv

2. Achieving large dynamic range control of gene expression with a compact RNA transcription-translation regulator.
A. M. Westbrook, J. B. LucksNucleic Acids Research. (2017).
Links: JournalPDFBioRxiv (Open Access)

3. Creating Small Transcription Activating RNAs.
J. Chappell, M. K. Takahashi, J. B. LucksNature Chemical Biology. (2015).
Links: JournalPDF

4. Rapidly characterizing the fast dynamics of RNA genetic circuitry with cell-free transcription-translation (TX-TL) systems.
M. K. Takahashi, J. Chappell, C. A. Hayes, Z. Z. Sun, J. Kim, V. Singhal, K. J. Spring, S. Al-Khabouri, C. P. Fall, V. Noireaux, R. M. Murray, J. B. LucksACS Synthetic Biology. (2014).
Links: JournalPDFBioRxiv (Open Access)

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