Seeing the light: Light-based approaches to control genes

Advances in pharmaceutical development have greatly increased our ability to treat disease, but side effects remain a major issue. Most pharmaceuticals attempt to mimic the action of a protein, but can cause side effects because they affect more than just their specific target. While studies on molecular understanding of pharmaceuticals appear promising for reducing side effects, pharmaceuticals are not the only answer for treating disease. As we learn more about disease states, it is clear that proper gene expression plays a role in disease development; thus, altering gene expression directly could provide another approach to treatment of disease.

Gene expression is a complex process that we are just beginning to understand. Gene expression has been the focus of a variety of research because it is now known that diseases are not always a result of a malfunctioning protein. Genetic diseases can arise from too much or too little of a protein. This means that controlling the amount of the protein being made is just as important as the protein itself. In a recent, surprising twist, a handful of research groups have been creating light-sensitive methods for controlling gene expression and, thus, protein production.

One way that gene expression is regulated is through the binding of gene regulators to DNA or RNA. This binding can block the transcription (DNA to RNA) or translation (RNA to protein) process. While the individual techniques vary between groups, the general principal behind controlling gene expression via light is similar -- researchers combine a light sensitive linker to the gene regulator, making the gene regulation light sensitive.  

This approach has proven successful at the transcription level. Researchers at North Carolina State University used a light activated cage to inhibit triplex-forming oligonucleotides, which bind to DNA, blocking its transcription. In the absence of light the triplex-forming oligonucleutides binds normally, but UV light blocks this binding. Lack of binding allows transcription of DNA; thus, light “turns on” gene expression.

Researchers at the University of Oregon paired up with Gene Tools LLC to develop a light sensitive use of morpholines. Morpholines bind to RNA and prevent protein synthesis. Using a light sensitive version of morpholine allowed these researchers to control gene expression at specific developmental time points creating a better understanding of the developmental time frame for gene expression in zebrafish.

Ideally, controlling gene expression could also be used as a treatment for disease. For example, diabetes patients could benefit if insulin production could be turned on. Researchers at ETH Zurich connected the GLP-1 signaling pathway, which effects insulin production and blood glucose levels, to light sensitive melanopsin. This allowed the presence of blue light to increase insulin production via GLP-1 pathways.

Controlling gene expression is a fascinating new approach to treatment and could provide a targeted approach to disease management. In addition to treatment, this approach could also greatly improve our understanding of the role of genes on a developmental time scale. Developmental research emphasizes the critical period for the function of genes, but it can be hard to tease apart acute and chronic effects. The ability to selectively and reversibly turn on or off a gene at a specific time and place could greatly improve our understanding of developmental effects; thus, the ability to turn on and off genes also provides a unique research tool for understanding the effects of genes in a developmental and region-specific way.