The Secret Life of MicroRNAs

By Alisa Kim

How does something so fundamental to the workings of the human body escape the scrutiny of biologists worldwide for so long?

If Dr. Burton Yang, a senior scientist in biological sciences at Sunnybrook Research Institute, were to hazard a guess, it would be akin to walking into a room and overlooking a speck of lint. "They're just so tiny," says Yang of microRNAs, a small class of ribonucleic acid (RNA) that regulate gene expression. "People thought they were just junk material within the cell. No one knew their function until 1993 when the two papers [outlining their discovery] came out."

The term "microRNA" was not coined until the early 2000s. "We now know that DNA (deoxyribonucleic acid) can produce a really small molecule—the smallest genetic material—and that this microRNA can regulate protein translation. When protein levels are regulated, this affects the activity of all our cells," says Yang.

In the last decade, scientists have discovered that microRNAs regulate which genes are expressed and when. They do this by destroying or interfering with messenger RNAs that code for proteins, thus lowering protein levels. MicroRNAs govern the expression of more than one-half of all human genes, including those responsible for cell growth and death, and play an important role in development, physiology and disease.

One of the challenges of this relatively new area of research stems from the expression of microRNAs in clusters; this makes it hard to identify the functions of a specific microRNA. Moreover, chemically synthetic microRNAs are easily damaged, making it impossible to obtain stable cell lines expressing microRNAs for long-term studies. "These difficulties may explain why there are relatively few microRNAs whose functions have been reported," says Yang.

He has overcome this hurdle by finding a way to study a microRNA in isolation. His lab has developed a technique to express a single microRNA in a Petri dish and in mice. He has also patented a technique that inhibits the function of individual microRNA, an important discovery in the development of treatments that require the silencing of a particular microRNA.

Yang is able to continue this line of inquiry thanks to a career investigator award from the Heart and Stroke Foundation worth $415,000 over five years. The aim of his research is to elucidate the roles of microRNAs in vascular development and diseases. Specifically, he will examine the activity of miR-17 and miR-378 in cell growth, tissue regeneration and the formation of new blood vessels.

Cells and proteins are the building blocks of blood vessels, but the proteins in blood vessels also play a role in the inflammation and scarring of damaged arteries. Yang's research seeks to uncover how these microRNAs regulate protein expression.

"Proper regulation of protein expression in blood vessels is essential to healthy functioning. We expect that these microRNAs will be promising as agents in promoting blood vessel formation and tissue repair involved in recovery from heart disease," Yang says.

Another intriguing aspect of this research is that one microRNA can have up to hundreds of gene targets, which means that the precise regulation of microRNAs must be achieved before therapies for various diseases can be developed. Yang says that knowing how to do this is a crucial next step. "MicroRNAs are very complicated, and we need to be careful. We may know that a particular microRNA regulates a gene in heart disease or tumour growth, but we don't know whether it also regulates some other genes. We don't want to create any problems for the body."