New research is helping to uncover a fundamental and longstanding question—how do epigenetic proteins regulate transcription and gene expression? The new findings reveal, more specifically, how the epigenetic signal H3K4me3 determines genetic regulation.

The study shows that H3K4me3 ensures genes are transcribed and activated at the right time in a controlled manner. Understanding how the signal functions in normal cells can also shed new light on the development of cancer—and the role played by a breakdown in the regulation of gene activity.

This research is published in Nature in the paper, “H3K4me3 regulates RNA polymerase II promoter-proximal pause-release.

It has been known for more than 20 years that the enzymes tagging DNA with H3K4me3 are crucial for normal cell development, as well as being linked to leukemia, breast, bowel, and pancreatic cancers. Until now, scientists lacked an understanding of the mechanism.

Now, research is uncovering how epigenetic proteins help regulate cell development and can be involved in cancer, how the process of gene expression is regulated, and how blocking epigenetic proteins could affect both normal and cancer cells.

Chemical modifications such as H3K4me3 (tri-methylation of histone H3 lysine 4) can turn genes on or off, and are often altered in cancer. Using mouse stem cells, researchers were able to achieve a complete loss of all H3K4 methylation. In doing so, they found that the H3K4me3 modification is essential for regulating how and when genes are expressed. By regulating the flow of RNA polymerase II, H3K4me3 determines when gene expression should start and the speed at which it runs. More specifically, they noted that “acute loss of H3K4me3 does not have detectable effects on transcriptional initiation but leads to a widespread decrease in transcriptional output, an increase in RNA polymerase II (RNAPII) pausing and slower elongation.”

“We have solved a 20-year-old puzzle by discovering how a well-known epigenetic modification controls gene expression,” noted Kristian Helin, PhD, professor and chief executive of the Institute of Cancer Research, London. “Because the enzymes determining the level of H3K4me3 in the cell frequently are found mutated in cancer, our studies could have implications for understanding and treating cancer.”

“This is what I call ‘textbook’ science—the aspiration of many scientists, including myself, to solve fundamental questions so that our discoveries go into textbooks,” Helin added. “Even the most cutting-edge treatments for patients are built on the foundations of fundamental scientific discoveries like this one. It is only thanks to basic understanding of how genes and cells work, and what can go wrong with them, that we can create the cancer treatments of the future.”

“Drugs targeting these ‘traffic lights’, or epigenetic modifications, such as H3K4me3, are already being developed—and it is possible that they could one day become an effective way of treating cancer patients. This is an exciting new avenue for cancer research, and we believe our findings will pave the way for more effective development of these epigenetic drugs.”

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