Scientists decode a key mutation in many cancers, highlighting the increased role of RNA in human gene expression

Inside every cell, inside every nucleus, your existence depends on an incredibly complicated dance. Proteins are constantly wrapping and unwrapping DNA, and even minor missteps can lead to cancer. A new study from the University of Chicago reveals a previously unknown part of this dance, which has important implications for human health.

In the study, published October 2 in Nature, a team of scientists led by Professor Chuan He of the University of Chicago, in collaboration with Professor Mingjiang Xu of the University of Texas at San Antonio, discovered that RNA plays an important role in how DNA is packaged and stored in your cells, via a gene. known as TET2. The article is titled “mRNA⁵C oxidation by TET2 regulates chromatin state and leukemogenesis.

This pathway also appears to explain a long-standing puzzle about why so many cancers and other disorders involve TET2-related mutations and suggests a set of new targets for treatments.

“This represents a conceptual advance,” said He, who is John T. Wilson, professor emeritus in the Department of Chemistry and the Department of Biochemistry and Molecular Biology and an investigator at the Howard Hughes Medical Institute.

“Not only does this offer targets for treatment of multiple diseases, but we add to the bigger picture of chromatin regulation in biology,” he said. “We hope the real-world impact will be very high.”

Revelations about RNA

His lab has made several discoveries that have changed our view of how genes are expressed. In 2011, they discovered that in addition to changes in DNA and proteins, changes in RNA could also control which genes are expressed.

Since then, he and his team have discovered more and more ways that RNA methylation is fundamentally involved in turning genes on and off in the plant and animal kingdoms.

With this in mind, they turned their attention to a gene called TET2. We’ve known for a long time that mutating TET2 or TET2-related genes causes all kinds of problems. These mutations occur in 10 to 60% of different cases of human leukemia and also appear in other types of cancer. The problem was that we didn’t know why, which significantly hampered the search for treatments.

Other members of the TET family act on DNA. For years, researchers have therefore been studying the effects of TET2 on DNA. But his lab discovered they had been looking in the wrong place: TET2 actually affects RNA.

When your cells print their own copies of your genetic material, they must be carefully packaged and folded for future reference; the packets are known as chromatin. If this doesn’t happen correctly, all sorts of problems can arise. It turns out that RNA plays a key role in this process and its role is controlled by TET2 through a modification process called methylation.

Through a series of clever experiments, deleting genes and observing what happened, the He lab team showed how it works. They discovered that TET2 controls how often a type of modification called m⁵C occurs on certain types of RNA, which attract a protein known as MBD6, which in turn controls chromatin packaging.

When you are an infant and your cells are actively dividing into different cell types, TET2 loosens the reins so that chromatin is more easily accessible and stem cells can develop into other cells. But as an adult, TET2 is meant to tighten the reins. If this repressive force is lost, MBD6 has carte blanche and devastation can ensue.

“If you have a TET2 mutation, you reopen this growth pathway that could eventually lead to cancer, particularly in the blood and brain, because this pathway appears to be the most important in blood and brain development,” said Hey.

As a final confirmation, the team tested human leukemia cells in petri dishes. When the team removed the cells’ ability to create MBD6, effectively pulling the reins, the leukemia cells all died.

“A miracle solution”

The most exciting aspect of this discovery for cancer researchers is that it gives them access to a whole new set of drug targets.

“What we hope to get from this is a silver bullet to selectively eliminate only cancer cells, targeting that specific pathway activated due to loss of TET2 or IDH,” said He, who works with the Polsky Center for Entrepreneurship and Innovation from UChicago. to found a start-up to create such a drug.

But we also know that TET2 mutations have consequences other than cancer. TET2 mutations also occur in a fraction of all adults over age 70 and contribute to an increased risk of heart disease, stroke, diabetes and other inflammatory diseases, a condition known as CHIP .

“These patients have TET2 mutant blood cells, but they haven’t yet caused cancer,” explained Caner Saygin, an oncologist and assistant professor of medicine at the University of Chicago who specializes in treating CHIP patients and also works with the He laboratory. on several projects.

“But these TET2 mutant cells are more inflammatory, and as they circulate, they lead to an increased risk of diseases such as heart, liver and kidney disease. At the moment, I cannot prescribe anything to these patients because they do not ‘don’t have cancer yet’, but if we could eliminate these mutant cells, we could improve their lives. »

A radical change

This discovery also represents a step change in our understanding of chromatin – and therefore gene expression as a whole.

Previously, we knew that a form of RNA methylation called m⁶A affects gene expression: its placement and removal affects chromatin packaging, which determines which portions of DNA are actually translated.

But if I⁵C is also in this category, suggesting that it is a general mechanism for controlling chromatin and gene expression, and there may be more. “If there’s a second one, you could have a third, a fourth, a fifth,” he said.

“This indicates that RNA modification on chromatin is a major mechanism for regulating chromatin and gene transcription. We believe this pathway is just the tip of the iceberg.”