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An innovative three-color method for capturing images of mRNA inside live mammalian cells has been developed by UMass Amherst chemists. Because RNA is both incredibly important to human life and health and poorly understood, the ability to tag disparate RNA with different colors and watch them, in real time, as they do their work is a giant step forward in understanding one of life’s basic building blocks. The study appeared recently in Nature Methods.
“There are many diseases that result from something going wrong with RNA,” says Daisy Pham, a graduate student in chemistry at UMass Amherst and the paper’s lead author. “And RNA plays a crucial role inside our cells: it’s the messenger that tells the cell how to make the proteins for which DNA is the master blueprint, they can turn on and off specific genes, they can organize and shape cellular structures, and other functions that need to happen perfectly for our cells to remain healthy.”
“We’re very curious about all of RNA’s many functions,” says Jiahui (Chris) Wu, assistant professor of chemistry at UMass Amherst and the paper’s senior author, “and the big question is how do you actually study them? The best answer is to actually observe them inside a living cell, but they’re tiny.”
One answer—if you specialize in fluorescent microscopy, as Wu does—is to make the individual RNA strands stand out from their background by tagging them with fluorescent markers and then peering at the glowing bits of cellular code through a powerful microscope.
Wu and Pham are quick to point out that there is currently a state-of-the-art, widely used way of doing this called the “RNA hairpin method,” that depends on fusing glowing fluorescent protein tags onto a targeted strand of RNA.
The UMass chemists have built upon this method in a few ways.
First, they designed glowing proteins that target a specific part of the RNA molecule and only glow when “plugged in” to the RNA strand. This differs significantly from traditional methods, which are “always on,” and can introduce background light pollution. Finally, Pham and Wu engineered three distinct glowing proteins that each light up in a specific color (green, red and far-red) to target specific kinds of RNA that perform distinct functions.
“We can now watch as different kinds of RNA in action inside a living cell,” says Pham, “and we can better understand how they do what they do.”
Reference: Pham TG, Ajayi O, He J, Sagarbarria I, Hardy JA, Wu J. Orthogonal RNA-regulated destabilization domains for three-color RNA imaging with minimal RNA perturbation. Nat Methods. 2025. doi: 10.1038/s41592-025-02905-x
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