Mighty micro RNAs

by Yi-Wen Chen, PhD, Children’s National Hospital, Washington DC

Many Nobel Prize-winning discoveries have contributed to the advancement of research and treatments for facioscapulohumeral muscular dystrophy (FSHD), and the work recognized in yesterday’s announcement follows in this tradition.

The Nobel Committee awarded the 2024 prize in physiology and medicine to Victor Ambros of UMass Chan Medical School and Gary Ruvkun of Harvard Medical School for their discovery of microRNA and its role in post-transcriptional gene regulation. The discovery was made in the 1990s after the two scientists completing their postdoctoral training at MIT studying anomalies in a tiny roundworm. They continued the studies in their own laboratories and discovered the first miRNA and the gene that is regulated by the miRNA. MicroRNA (miRNA) is today a focus of research in hundreds of centers around the world, including several FSHD labs such as my own, Scott Harper’s and Nizar Saad’s.

What is miRNA?

As we know, our cells are the basic unit of our body. Within each cell, genetic information stored in our DNA is passed onto messenger RNAs (mRNAs) via a process called transcription. Then the mRNAs are used for making proteins via a process called translation. Proteins are used to build the cells and maintain cell functions.

miRNAs are a special group of small RNA molecules that can intercept the mRNAs and control how much protein is made from these mRNAs. Because these small RNA molecules are very tiny (usually ~21-23 nucleotides) in comparison to other RNAs (which have hundreds to thousands of nucleotides), they were named micro RNAs (miRNAs, not to be confused with mRNA, or messenger RNA).

miRNAs bind to their target mRNAs and usually stop or reduce protein production by sequestering the mRNAs away from the translation machinery or by directly destroying the mRNAs with the help of a group of specialized proteins. Although the exact number is difficult to know, there are more than 2,000 different miRNAs in our cells. Each miRNA can regulate the production of a specific groups of proteins.

Do miRNAs have a role in FSHD?

Several miRNAs have been reported to be altered in cells and blood samples collected from individuals with FSHD. The altered miRNAs appear to regulate various types of proteins, including those made only in muscles and proteins regulating inflammation and other cellular functions. The changes of the miRNAs are believed to be either directly caused by the expression of DUX4 (the gene causing FSHD) or secondary changes due to the disease process (such as muscle damage and inflammation). Understanding these miRNA changes can lead to better understanding of disease mechanisms and therapeutic development.

In addition to understanding disease mechanisms, researchers study miRNAs altered in FSHD to identify circulating biomarkers for FSHD. For those miRNAs discovered in blood samples, researchers are evaluating the feasibility of using them to inform therapeutic efficacy, for example whether a treatment corrects the miRNA differences between FSHD patients and healthy individuals.

For therapeutic development, researchers are studying miRNAs that can regulate the production of the DUX4 protein and are developing modified miRNA molecules that stop or reduce the production of DUX4 protein.

In summary, miRNAs are small RNAs that play important roles in regulating cell functions and maintaining health. Many research activities are centered at the miRNAs altered in FSHD currently, including understanding disease mechanisms, biomarker development, and therapeutic intervention.