by An important new study in the journal Nature reveals a “traffic light” mechanism that controls genetic activity inside cells — a system that could potentially be targeted by cancer drugs already in development.
The research describes how “epigenetic” changes in DNA structure can act as a stop signal to determine whether a gene needs to be read.
Unlike our genetic makeup, which is well understood, the world of epigenetics is still largely unexplored and referred to as the “dark matter” of the genome.
But the new findings answer a fundamental and long-standing question — how epigenetic proteins regulate the transcription and gene expression processes by which our genes are read and translated into proteins.
Scientists at the Institute of Cancer Research London today (Wednesday) reveal how a key epigenetic mark called H3K4me3 — determines when and how DNA should be read and translated into proteins inside our cells.
The study shows that H3K4me3 ensures that genes are transcribed and activated at the right time in a controlled manner, like a set of traffic lights regulating the flow of cars on a busy road. Understanding how it works in normal cells may also shed new light on cancer development — and the role that splicing plays in regulating gene activity.
It has been known for more than 20 years that the enzymes that place H3K4me3, a chemical tag added to DNA, are crucial for normal cell growth, and are also linked to leukemia, breast, colon and rectal cancer. pancreas. But until now, scientists lacked an understanding of what the chemical tag does, despite years of research.
The new “textbook discovery,” as described by the researchers, is transforming our understanding of:
- how epigenetic proteins help regulate cell growth and may be involved in cancer
- how the process of gene expression is regulated — decoding DNA into functional proteins used by our bodies
- how blocking epigenetic proteins could affect both normal and cancer cells.
The long-term hope is that this new understanding could lead to a new class of cancer therapies that target epigenetic “traffic lights” to block the activity of genes that may fuel cancer.
The study was funded by the Institute for Cancer Research (ICR) itself and the Memorial Sloan Kettering Cancer Center.
Epigenetics affects the activity or expression of genes without changing the underlying genetic code — for example, by adding or removing chemical tags or modifications to DNA or proteins around which DNA is wrapped, called histones. 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 and sophisticated genetic and biochemical experiments in the laboratory, researchers found that H3K4me3 modification is essential for regulating how and when our genes are expressed.
The team found that H3K4me3 acts like a traffic light at a busy junction. By regulating the flow of RNA polymerase II — a protein complex that reads and decodes DNA — H3K4me3 determines when gene expression should begin and the speed at which it occurs.
When given the green light, H3K4me3 allows RNA polymerase II to move along the DNA, transcribing it into RNA as it moves. But without H3K4me3, RNA polymerase II sticks to specific spots on the DNA, creating a hold and slowing transcription.
Previous results have shown that disrupting or altering H3K4me3 levels in cells is important for cancer development and affects response to therapy.
Study leader Professor Kristian Helin, Chief Executive of the Institute of Cancer Research London and a world leader in the study of epigenetics, said:
“Our study provides a fundamental new understanding of epigenetics, a very exciting and still largely unexplored area of cancer research. We have solved a 20-year-old puzzle by discovering how a known epigenetic modification controls gene expression. Because the enzymes that determine the level of H3K4me3 in the cell is often found mutated in cancer, our studies could have implications for understanding and treating cancer.
“This is what I call “textbook” science — the ambition of many scientists, myself included, to solve fundamental questions so that our discoveries make it into the textbooks. Even the most cutting-edge treatments for patients rest on a foundation of fundamental scientific breakthroughs like this. It is only through a 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 that target these ‘traffic lights,’ or epigenetic modifications, like H3K4me3, are already being developed — and it’s possible that one day they could become an effective way to treat cancer patients. This is an exciting new avenue for research into cancer, and we believe that our findings will pave the way for more effective development of these epigenetic drugs.”
