BMB Blog

To celebrate RNA Day (August 1^st), we are featuring the work of our own Professor Thoru Pederson. Pederson has studied RNA since he was a graduate student in the late 1960’s and has made several important discoveries about this fundamental molecule since then.

When asked what RNA-focused research he wanted to highlight from across his entire career, he chose a more recent set of scientific advances. 

“In 2016-2018, my lab undertook extensive RNA remodeling, something we had not had reason to do anytime previously, or at least not to such a degree.” But before we get into what Pederson and his lab did, let’s first discuss what he means by “RNA remodeling.”

RNA is the key intermediate between DNA (the information storage system of our cells) and proteins (the machines in our cells that make things happen). 

When a cell needs to make a new protein, the blueprints are transcribed from the code of DNA to the very similar code of RNA. This RNA, termed “messenger RNA,” can then be translated into the completely different language of peptides that string together to make proteins. However, messenger RNA isn’t the only kind of RNA in the cell. All the different types of RNA carry out unique and important functions. For RNAs to do their many jobs in the cell, they have to be able to bind to both DNA and to proteins. This puts RNA molecules in the unique position of being able to physically interact with and regulate many different kinds of molecules within a cell, making them the perfect candidates for biomedical engineering (how scientists make changes to existing biological machinery to solve problems related to human health).

“Remodeled” or edited RNA molecules are used by scientists to do all sorts of things, including studying human diseases in model organisms; creating cells that can biomanufacture important molecules; monitoring protein, RNA, or DNA levels within a cell; and more^1,2.  

Pederson was motivated to use RNA as a tool to investigate his other great scientific passion: understanding how and why DNA moves around in the nucleus of the cell. 

We can think of the nucleus like New York City – it is absolutely packed full of DNA and other molecules, just like NYC is packed full of people and rats. Now imagine the only view you’ve ever had of NYC is from an airplane six miles up in the air. You can assume from your general understanding of the world that there are people living in NYC and that they move around within the city throughout the day. However, there is almost no way to know where people are going within the city and why from just looking at a static sky-high photograph. To find out where people are going and why, you would need to get much closer to the city. Unfortunately, although we know there is DNA inside the nucleus and that it wiggles around during the day, we don’t have the option of getting closer to the mean streets of the nucleus.

Since the Magic School Bus doesn’t exist in the real world, scientists like Pederson and his lab member Dr. Hanhui Ma have to get creative if they want to understand how DNA structure is regulated and what that might mean for the cell. 

Since we’re stuck at a “sky-high” view of the nucleus, Pederson and Ma decided to find a way to track individual DNA sequences as they move around in the nucleus in real time. Sticking to our NYC example, this would be like putting GPS trackers on a group of people in the city. Watching a movie of their movements from the sky, we might be able to see them all moving into the financial district during the day and then dispersing back into the city at night. Knowing where the financial district is and what people usually do there, we would be able to conclude that the population we tracked was in fact a group of finance professionals.

So how can this be done inside a cell? 

This is where Pederson and Ma’s RNA remodeling comes into play. They took a sequence of RNA that was engineered to bind a specific DNA sequence and added on an extra string of RNA at the end. That extra string was designed to bind to glow-in-the-dark proteins that would then trail along with the DNA sequence as it moved around the nucleus. This special complex of RNA and glowing protein would then allow Pederson and Ma to take videos of a single cell and watch how the DNA (marked by the GPS tracker-equivalent complex of RNA and glowing protein) moved around in the nucleus³.

But this one innovation wasn’t enough to meet the ambitious goals of Pederson and Ma. 

Building off the innovations and discoveries of other scientists, Pederson and Ma developed an RNA-based technology called CRISPRainbow³. The goal of this technology was to enable the labeling of multiple different pieces of DNA in the nucleus simultaneously.

Pederson and Ma designed multiple different extra strings of RNA that all bound to different glowing proteins. Mixing together different combinations of RNA strings allowed them to make six different colors that could then be used to track six different DNA sequences as they moved around the nucleus all at the same time.

They then expanded this work by adding more repeats of RNA strings so that more and more glowing proteins would follow the corresponding DNA sequence around, increasing the brightness and creating better videos⁴.

These innovations are a true celebration of the versatile abilities of RNA.  

This feat of bioengineering has helped other scientists learn critical new things about how our cells work. For example, technologies like this help scientists learn about how our cells become and remain specialized to do important jobs in our bodies. In fact, problems with the organization and movement of DNA within our cells are linked to cancer.

To learn more about Dr. Pederson’s work, check out his lab website here. To learn more about RNA-focused research in our department, check out our Gene Expression & Epigenetics research category webpage.