University of Chicago scientists have discovered a new gap in our understanding of how our genes work. The team, led by Chuan He, John T. Wilson Distinguished Service Professor of Chemistry, Biochemistry, and Molecular Biology at UChicago, shed light on a long-standing mystery that has to do with a common way our genes are modified, known as RNA methylation.
Published January 27 in Science, The finding could have implications for gene therapies for diseases, as well as our view of gene expression, development, and evolution.
change of course
For more than a decade, Chuan He’s lab has focused on solving the mystery of a phenomenon called RNA methylation, which we are increasingly understanding plays a key role in our bodies and lives – from cancer to PTSD to aging .
In the 20th century we thought that DNA was the blueprint for the cell and from there everything is faithfully copied and executed. But little by little we began to learn that this is not the whole picture. DNA is the basic instruction manual, but our body responds to our experiences and the environment by turning some genes on and off as needed. For example, our skin can respond to sun exposure by producing more melanin, which protects the skin; or a plant may change its growth pattern during periods of drought to become shorter and thus require less water.
One way our bodies do this is through a process called RNA methylation, which He’s lab has been working on deciphering since 2010.
Generally, the RNA copies the DNA and relays the instructions to the cell to make various proteins. But the RNA changes those instructions along the way. One way to turn a specific gene on or off is to attach a small molecule called a methyl group to the messenger RNA. This change, known as methylation, modifies the instructions being carried out – altering the course of how your DNA is expressed.
Scientists knew this was important, but they didn’t know exactly how the process works inside cells. How does the cell choose the sites to be methylated?
“This is an incredibly important process that occurs in everything from fish to cows to us – so some cells become skin and some become eyes and some become muscles – but we lacked understanding of the mechanism itself,” He said. “For example, we could see that only a small part of the genetic sequence is methylated, but we didn’t know how those specific sites are selected.”
His group discovered that cells do not select certain sites for methylation; rather, they choose where not to methylate. And they believe the mechanism lies in the joints of the messenger RNA.
After the RNA copies the DNA in your cell, it is sliced up. Some parts of the messenger RNA are cut out, and the remaining parts are glued together and bound by a molecule called the “exon-joining complex”.
The team found that these exon-connecting molecules have an impact on whether or not a certain section of messenger RNA can be methylated. If the pieces of RNA are short, the two bulky molecules at either end will block any methylation. But longer pieces of RNA with more space between them are exposed and can be methylated.
The discovery could have major implications for both biology and medicine, the authors explained.
“A Significant Discovery”
One possible impact has to do with artificial genes. For gene therapies for cancer and other diseases, and for basic research to understand how biology works, scientists often create sections of artificial genes and send them into cells. For example, if a patient’s tumor is getting out of control, scientists could engineer an artificial gene that would tell them to stop. But the way scientists have made these artificial genes so far doesn’t involve exon junction complexes in the RNA. Because the exon junction complexes play such an important role in normal gene expression, omitting them could have implications that scientists hadn’t considered.
“When people design reporters for gene expression or even in gene therapy, there’s this extra layer of regulation that you have to consider in the design,” He said. “Without this packaging, it could become hypermethylated, meaning it’s not an exact mimic of the natural process.”
The discovery is also a major step forward in our understanding of biology and evolution, he said.
The team observed evidence of this process in everything from zebrafish to humans, but not in shellfish or insects. “So vertebrates may have evolved this to optimize the stability of their genetic material,” he explained.
For example, human brain tissue and heart tissue have vastly different amounts of exon junction complexes. That means it could play a role in how cells differentiate as they develop from an embryo, He said.
“This discovery points to a new level of gene expression regulation and a new way to regulate the stability of mRNA in general,” He said. “We will take a long time to understand the full impact.”