Modifying gene expression through riboswitches

Messenger RNA (mRNA), the RNA transcribed from a DNA template in order to make proteins, contains elements able to sense and bind to specific targeting molecules (metabolites or metal ions). In bacteria, fungi and plants, these binding mechanisms are used to control gene expression, and therefore act as genetic "switches", which is why these RNA elements are called "riboswitches". They are often found at the 5' end of the mRNA, in the untranslated region (the stretch that precedes the start codon): this way, they are the first domain to be synthesized and can therefore influence expression before the entire mRNA is created.

Riboswitches have two components: the domain that binds to the ligand is called "aptamer" and it's highly conserved from an evolutionary point of view, as it has to "sense" a precise type of molecule. The other component, called "expression platform," is what regulates gene expression, and, contrary to the aptamer, it can vary greatly in order to affect the different processes of transcription, translation, and RNA processing.

In order to understand how riboswitches bind to their specific ligands, it is vital to decipher their "secondary structure," in other words, the way they fold and assume a 3-D structure that allows them to "sense" and "capture" the targeting molecules. Common elements of RNA secondary structures are "helices" (similar to those found in DNA), and "hairpins," which take place when the RNA folds back onto itself. "Some riboswitches are surprisingly complex, and they rival protein factors in their structural and functional sophistication [1]."

The following figure, from this Scitable article, illustrates the kind of changes in secondary (3D) structure a riboswitch can undergo before and after binding to a molecule. 

A riboswitch can adopt different secondary structures to effect gene regulation depending on whether ligand is bound. This schematic is an example of a riboswitch that controls transcription. When metabolite is not bound (-M), the expression platform incorporates the switching sequence into an antiterminator stem-loop (AT) and transcription proceeds through the coding region of the mRNA. When metabolite binds (+M), the switching sequence is incorporated into the aptamer domain, and the expression platform folds into a terminator stem-loop (T), causing transcription to abort. aptamer domain (red), switching sequence (purple), and expression platform (blue).

Because they affect gene expression, particularly genes involved in biosynthetic pathways, riboswitches are natural targets for drug development.

"First, many riboswitches repress the expression of genes whose protein products are involved in the transport or biosynthesis of essential metabolites. Therefore, compounds that trick riboswitches by mimicking the natural ligand might inhibit bacterial growth by starving the cells for that essential metabolite. Second, medicinal chemists already have a ‘‘hit’’ compound (the natural ligand) for each validated riboswitch class that they can begin to chemically alter to create new antibiotics. In this regard, riboswitches are almost unique among noncoding RNAs classes because they have evolved pockets to purposefully bind a small molecule, and therefore should be more easily drugged [1]."

From the Scitable article:

"Their role in regulating transcription in bacteria makes them enticing targets for the development of novel antibiotics aimed at stopping bacterial pathogens from flourishing inside the people they infect. Because riboswitches control genes essential for bacterial survival, or genes that control the ability of bacteria to succeed at infection, a drug designed to affect a riboswitch could be a powerful tool for shutting down pathogenic bacteria."

Synthetic riboswitches have been developed and shown to activate or repress gene expression in bacteria [2]. While I couldn't find any studies done in humans yet (though if you guys know of some, please let me know!), I did find a Nature letter reporting the first ever human RNA switch analogous to riboswitches [3].

[1] Breaker, R. (2011). Prospects for Riboswitch Discovery and Analysis Molecular Cell, 43 (6), 867-879 DOI: 10.1016/j.molcel.2011.08.024

[2] Topp, S., Reynoso, C., Seeliger, J., Goldlust, I., Desai, S., Murat, D., Shen, A., Puri, A., Komeili, A., Bertozzi, C., Scott, J., & Gallivan, J. (2010). Synthetic Riboswitches That Induce Gene Expression in Diverse Bacterial Species Applied and Environmental Microbiology, 76 (23), 7881-7884 DOI: 10.1128/AEM.01537-10

[3] Ray, P., Jia, J., Yao, P., Majumder, M., Hatzoglou, M., & Fox, P. (2008). A stress-responsive RNA switch regulates VEGFA expression Nature, 457 (7231), 915-919 DOI: 10.1038/nature07598