Altering MicroRNA Function

Image courtesy of Qiagen.

Have you ever wanted to do something, just because you were told you can’t do it? Worry not—people aren’t the only ones susceptible to reverse psychology. Even at the level of our own cells, forcing little rebellious RNAs to “clean their [molecular] bedroom” isn’t always straightforward. But a pair of trained eyes can dream up the right techniques.

Alex Svoronos and Donald Engelman weren’t always the microRNA experts they are today. While working on a separate project for his PhD in Biomedical Engineering in Engelman’s lab at Yale, Svoronos noticed something strange about these small non-coding sequences. MicroRNAs control gene expression by silencing the signals carried by messenger RNAs (mRNA) before they can be translated into protein. But while examining literature about the genes they affect, Svoronos found some contradictions. “[One paper] would say a specific microRNA’s function was one thing, while another paper would claim it to have a completely opposite function,” Svoronos said. 

With their interests piqued, the researchers randomly selected microRNAs referenced at least fifty times across various publications. “We observed conflicting reports for eighty-five percent of the microRNAs we looked up,” Svoronos said. Wanting to further explore these inconsistencies, the Yale researchers selected miR-125b—a known regulator of genes associated with cell proliferation, apoptosis, and metastasis—as their microRNA guinea pig. 

Computational and mathematical modeling combined with cell experiments revealed something incredible: the initial relative amount of miR-125b’s target genes in the cell determines which gene the RNA silences. For example, if a greater concentration of genes that inhibit apoptosis are originally present in the cell, miR-125b will silence these genes and therefore promote apoptosis. On the other hand, if a greater proportion of genes expressed are pro-apoptotic, the molecule will inhibit these genes and prevent apoptosis. Seemingly changing its mind depending on what’s most popular, our rule-breaking miR-125b simply can’t stick to the status quo. 

Looking forward, Svoronos and Engelman are exploring applications of their new understanding. But knowing we can one-eighty the role of microRNA in a cell by expressing more of one target gene or another fundamentally changes how we view these molecules. MicroRNAs’ ability to selectively silence cancer genes could be exploited in the development of new anticancer drugs, vaccines, and other therapies. And as Alex Svoronos parts with the Engelman lab to complete his medical residency in ophthalmology, his PhD work will hopefully follow him, as the next decade brings about microRNA therapeutics to treat disorders of the eye. 

Our understanding of microRNAs still needs to grow up quite a bit. But as researchers explore potential avenues, they can take a lesson from microRNA’s book and know it’s always alright to change their minds one, two, four, or sixteen times.