Understanding RNA “Dance” will guide future RNA Therapeutics

Dr. Alan Chen from the RNA Institute at the University At Albany, New York, published today in Nature findings that show structural changes in an RNA molecule involved in genetic imbalances plays a significant role in the control of protein production in the cell. Leveraging these findings will help design better targets for RNA guided therapeutics in the future.

MicroRNAs (miRNAs) are short 22 nucleotide snippets of genetic material responsible for regulating gene-expression in humans, and many diseases such as cancer have been linked to dysregulation of miRNA levels. A single miRNA can target dozens of different mRNA sequences, and each mRNA can be regulated by multiple miRNAs simultaneously, resulting in the synchronized fine-tuning of complex genetic networks. A key protein called Argonaut (hAGO) plays the role of the molecular “matchmaker”, by loading miRNAs and deciding which mRNAs will be targeted via poorly understood mechanism.

Currently, the only sure-fire way to tell which mRNAs are affected by which miRNAs is to fish for them individually in massive genetic screens, an incredibly noisy and labor-intensive process. Being able to predict ahead of time which microRNAs are most likely to affect a given messenger RNA would be a tremendously useful tool for advancing genetic research.

“To crack the microRNA code we need to understand which of the 2,000+ miRNAs regulate which of the 12,000+ mRNAs,” explains Alan Chen.

Simulation models guided by NMR experiments reveal two different conformations microRNA-mRNA complexes can fit snugly in the Argonaut protein

Dr. Chen, in collaboration with Dr. Petzold at the Karolinska Institutet, used a combination of Nuclear Magnetic Resonance (NMR) experiments and computer simulations to show that mRNAs are able to rapidly switch between two very different conformations, and that both of these conformations fit snugly in the Argonaut protein. The work relied heavily on structural models created by co-author Parisa Ebrahimi, a graduate student in Dr. Chen’s lab, who designed massive all-atom simulations of the microRNA-mRNA complexes guided by NMR data from Dr. Petzold’s lab, an endeavor that required millions of cpu-hours of supercomputer time.

“We now think part of the requirement is that the right RNA partners are able to do this “dance” switching rapidly between the two different poses”, Dr. Chen explains. This was confirmed in the published work by testing an additional 5 microRNA/mRNA pairs with sequences allowing for conformation switching, and in each case mutating the complex to freeze it in the highly bent shape actually increased downregulation potency in live-cell culture.

Dr. Chen’s research developing computer simulations of RNA structure and function are supported via grants from the National Science Foundation and National Institutes of Health.

Publication: “Base-Pair Conformational Switch Modulates miR-34a Targeting of Sirt1 mRNA”. Lorenzo Baronti, Ileana Guzzetti, Parisa Ebrahimi, Sarah Friebe Sandoz, Emilie Steiner, Judith Schlagnitweit, Bastian Fromm, Luis Silva, Carolina Fontana, Alan A. Chen and Katja Petzold. Nature, online 27 May 2020, doi: 10.1038/s41586-020-2336-3

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