Your survival is dependent upon an extraordinarily intricate dance that takes place within every cell and inside every nucleus. DNA is continually being wrapped and unwrapped by proteins, and even little mistakes might result in cancer.
An aspect of this dance that was previously unknown and that has important health ramifications for people is revealed by a recent study from the University of Chicago.
Their findings were published in the journal Nature.
Using a gene called TET2, a group of researchers led by Chuan He, a professor at the University of Chicago, and Mingjiang Xu, a professor at the University of Texas Health Science Centre at San Antonio, discovered that RNA significantly influences the way DNA is packed and stored in your cells. Along with offering a list of potential new therapy targets, this route also seems to explain the long-standing mystery of why TET2-related mutations are present in so many malignancies and other illnesses.
This represents a conceptual breakthrough,
Not only does it offer targets for therapy for several diseases, but we are adding to the grand picture of chromatin regulation in biology,
We hope the real-world impact is going to be very high.
John T. Wilson
Several findings from his group have challenged our understanding of how genes are expressed. In 2011, they showed that, in addition to alterations to DNA and proteins, modifications to RNA may also regulate what genes are expressed.
Since then, He and his colleagues have discovered an increasing number of ways in which the expression of certain genes in both the plant and animal kingdoms is largely determined by RNA methylation.
With this perspective, scientists shifted their focus to a gene called TET2. We’ve known for a very long time that mutations in TET2 or TET2-related genes cause a variety of issues. These mutations show up in various forms of cancer as well as 10–60% of instances of human leukaemia. The issue was that we were unable to determine the cause, which seriously impedes the search for solutions.
Researchers have been examining TET2’s impact on DNA for years since the other members of the TET family also act on DNA. However, His lab discovered they had been hunting in the incorrect spot: TET2 really has an impact on RNA.
The genetic material that your cells print on their own has to be carefully folded and packed for future use; these packages are called chromatin. Mistakes of such kind can lead to a host of problems. It turns out that TET2 regulates the function of RNA, a crucial component in this process, by a process known as methylation.
The He lab team demonstrated how this functionsed by deleting genes and seeing the results through a series of ingenious experiments. They discovered that TET2 regulates the frequency of a certain kind of alteration called m5C on particular RNA types. This modification draws a protein called MBD6, which regulates chromatin packing.
If you have a TET2 mutation, you reopen this growth pathway that could eventually lead to cancer—especially in the blood and brain, because this pathway looks to be most important in blood and brain development,
Prof. Chuan He
The group examined human leukaemia cells in petri plates for one last check. The leukaemia cells all perished when the researchers took away the cells’ capacity to produce MBD6, essentially yanking on the reins.
For cancer researchers, the most intriguing aspect of this discovery is that it opens up a whole new range of potential therapeutic targets.
What we hope we can get from this is a silver bullet to selectively get rid of just cancer cells, by targeting this specific pathway activated because of TET2 or IDH loss,
Prof. Chuan He
However, it’s also known that TET2 mutations can result in conditions other than cancer. A portion of persons over the age of 70 also had TET2 mutations, which raise the risk of diabetes, heart disease, stroke, and other inflammatory diseases as well as CHIP.
These patients have TET2 mutant blood cells, but they haven’t yet caused cancer,
But these TET2 mutant cells are more inflammatory, and as they circulate, they cause an increased risk for things like heart, liver, and kidney diseases. Right now, I cannot prescribe anything to these patients because they don’t have cancer yet, but if we could eliminate those mutant cells, we could improve their lives.
Caner Saygin
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The discovery also represents a fundamental shift in our knowledge of chromatin and, by extension, gene expression in general.
It was previously known that a particular kind of RNA methylation known as m6A influences the expression of genes by altering the packing of chromatin, which determines which DNA sequences are translated into actuality.
Source: The University of Chicago – News
Journal Reference: Zou, Zhongyu, et al. “RNA M5C Oxidation by TET2 Regulates Chromatin State and Leukaemogenesis.” Nature, 2024, pp. 1-9, DOI: https://doi.org/10.1038/s41586-024-07969-x.
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