Researchers Discovered the Start and Stop Controls of Gene Expression

For years, scientists have been trying to understand how a particular histone modification called H3K4me3 affects gene expression. Although it is known to play a role in activating genes, its precise function has been difficult to determine due to the presence of other similar proteins within the cell that have overlapping functions.

Recently, however, the elusive function of H3K4me3 has finally been revealed. According to an article published in the journal Nature, this histone modification acts as a signaling system to regulate gene expression, basically controlling the start and stop of gene expression. This new discovery which is being hailed as a significant breakthrough has transformed our understanding of how epigenetic proteins regulate cell development and their potential role in cancer. It has also shed new light on the process of gene expression and suggests that blocking epigenetic proteins may impact normal and cancer cells.

The study, which was conducted at the Institute of Cancer Research (ICR) in London, utilized advanced genetic and biochemical techniques on mouse stem cells to investigate the specific role of H3K4me3. They found removal of the proteins responsible for adding the modification resulted in a loss of all H3K4 methylation. They also discovered that H3K4me3 controls the release of RNA polymerase II, an enzyme that helps transcribe DNA.

Like a traffic light at a busy intersection, the H3K4 modification controls the flow of this enzyme, determining when it should begin and the speed at which it operates. In the absence of H3K4me3, RNA polymerase II becomes stuck at specific points on the DNA, resulting in transcription delays. These findings imply that altering H3K4me3 levels in cells could have implications for cancer development and treatment response.

“Our study offers a fundamental new understanding of epigenetics, a very exciting and still largely underexplored area of cancer research,” said Professor Kristian Helin, Chief Executive of ICR and lead investigator. “We have solved a 20-year-old puzzle by discovering how a well-known epigenetic modification controls gene expression. 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.”

Helin refers to the findings as “textbook” science, indicating that they are essential to research in the field of epigenetics and will be incorporated into textbooks as the foundation for advanced research and practical applications.

He stated, “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 or genes and cells work, and what can go wrong with them, that we can create the cancer treatments of the future.“

According to the researchers, the development of drugs that target these “traffic lights” or epigenetic modifications, such as H3K4me3, is already underway, potentially providing an effective treatment option for cancer patients.

“This is an exciting new avenue for cancer research,” says Heilin, “And we believe our findings will pave the way for more effective development of these epigenetic drugs.”

Source: Hua Wang, et al. H3K4me3 regulates RNA polymerase II promoter-proximal pause-release. Nature, 2023; DOI: 10.1038/s41586-023-05780-8

Reference: New study unveils epigenetic ‘traffic lights’ controlling stop and go for gene activity. Institute of Cancer Research. MAR 2023

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