A New Understanding of Chromatin Regulation and its Implications

Human survival is dependent upon an extraordinarily intricate dance that takes place inside every cell and every nucleus. DNA is continually being wrapped and unwrapped by proteins, and even small mistakes might result in cancer.

An aspect of this dance that was previously unknown is revealed by a recent University of Chicago study, and it has important health consequences for people.

Scientists led by Chuan He of the University of Chicago and Mingjiang Xu of the University of Texas Health Science Center at San Antonio discovered in their study, which was published in the journal Nature, that RNA significantly influences the way DNA is packaged and stored in human cells through a gene called TET2.

Along with offering a list of potential new treatment 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.”

Chuan He, John T. Wilson Distinguished Service Professor and Investigator, Howard Hughes Medical Institute

RNA Revelations

Several findings from his group have challenged the understanding of how genes are expressed. In 2011, it was discovered that alterations to RNA, in addition to changes to DNA and proteins, may also regulate gene expression.

Since then, he and his colleagues have discovered an increasing number of ways in which RNA methylation largely determines the expression of certain genes in both the plant and animal kingdoms.

Using this perspective, they focused on a gene known as TET2. It has been known for a very long time that mutations in TET2 or TET2-related genes cause a variety of issues. These mutations show up in other forms of cancer and 10–60% of cases of human leukemia. The issue was that humans were unable to determine the cause, which seriously impeded the search for solutions.

The other members of the TET family act on DNA, so researchers have been looking at TET2’s effects on DNA for years. However, his lab discovered they had been hunting in the incorrect spot: TET2 impacts RNA.

The genetic material that cells print on their own needs to be carefully folded and packaged for future use; these packages are called chromatin. Mistakes of that 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 functioned by deleting genes and observing 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 packaging.

TET2 releases some of the constraints during infancy, allowing stem cells to differentiate into different cell types and chromatin to be more readily accessed. However, TET2 is meant to tighten the screws once an adult. MBD6 has unrestricted access if that suppressive force is removed, and chaos may result.

“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,” said He.

The group examined human leukemia cells in Petri dishes for one last check. The leukemia cells all perished when the researchers removed the cells' capacity to produce MBD6, essentially yanking on the reins.

“A Silver Bullet”

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,” said He

He is also working with UChicago’s Polsky Center for Entrepreneurship and Innovation to found a startup company to create just such a drug.

However, it is also known that TET2 mutations can result in conditions other than cancer. TET2 mutations also occur in a fraction of all persons older than 70 and contribute to a greater risk of heart disease, stroke, diabetes, and other inflammatory disorders, a condition known as CHIP.

These patients have TET2 mutant blood cells, but they have not 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 do not have cancer yet, but if we could eliminate those mutant cells, we could improve their lives.”

Caner Saygin, Oncologist and Assistant Professor, University of Chicago Medicine

Caner Saygin is specialized in treating CHIP patients and is also working with the He lab on several projects.

A Radical Change

The discovery also represents a fundamental shift in the knowledge of chromatin and, by extension, gene expression in general.

It was previously known that a particular type 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.

If m⁵C is also in this category, it shows this is a generic way to control chromatin and gene expression, and there could be others.

If there is a second, you could have a third, fourth, fifth. This says that RNA modification on chromatin is a major mechanism for chromatin and gene transcription regulation. We think this pathway is just the tip of the iceberg.”

Chuan He, John T. Wilson Distinguished Service Professor and Investigator, Howard Hughes Medical Institute