Epigenetic “traffic lights” Could Expand Our Knowledge on How Cancers Work banner
Home / Insights / Epigenetic “traffic lights” Could Expand Our Knowledge on How Cancers Work

Epigenetic “traffic lights” Could Expand Our Knowledge on How Cancers Work

By Dan Hilton
Epigenetic “traffic lights” Could Expand Our Knowledge on How Cancers Work

Since the discovery of the structure of DNA, the accepted central dogma of molecular biology states that the genetic information contained in our DNA is transcribed into short-lived messenger RNA, which is translated into the proteins that carry out the vast majority of our cellular functions.

Remarkably, all of our cells contain essentially the same DNA, but clearly cell types and functions differ. For example, a liver cell needs to perform a completely different role to a brain cell, but both contain the same genes. The intricate control of gene expression is at the heart of cell differentiation and development, and gene dysregulation can have serious implications, often resulting in cancer.

A recent study in Nature has revealed that a “traffic light” mechanism is involved in regulating gene expression, which could be potentially be targeted to treat cancer. The study describes how epigenetic markers can act as a signal in determining whether a gene should be expressed.

What is epigenetics?

Epigenetics is the study of heritable changes in gene activity that does not involve the modification of the underlying DNA sequence. As well as inheriting genetic information, cells also inherit information that is not encoded in the sequence of DNA: this is epigenetic information. One way that epigenetic information manifests is via the chemical modification of histone proteins, which package long spools of DNA into tightly wound chromatin in our cells.

These chemical modifications on the protruding tails of histone proteins are thought to regulate gene expression by acting as a landing pad for other proteins, which may then be involved in the activation or repression of gene expression. For example, epigenetic modifications may interact with regulatory factors, such as transcription factors and non-coding RNAs to coordinate the expression or repression of genes. Furthermore, whether a gene is expressed or not is thought to be partly determined by the local structure of chromatin. When viewed under a microscope, isolated chromatin appears as beads on a string; the string corresponding to naked DNA and the beads corresponding to DNA wound around histone proteins. It has been demonstrated that the “beads” of histone proteins are in fact highly dynamic, continually moving position along DNA, bunching up to produce a highly condensed network, or relaxing into a more open, accessible structure.

Consequently, the presence or absence of epigenetic modifications on histone proteins can play a major role in the dynamic remodelling of chromatin, to create an environment suitable for gene activation or indeed gene repression. However, arriving at any meaningful conclusions has thus far proven challenging due to the transient nature of epigenetic events.

Epigenetic modifications can act as a ‘traffic light’ for gene expression.

Returning to the results of the new study, scientists at the Institute of Cancer Research have demonstrated that a key epigenetic modification known as trimethylation of histone H3 lysine 4 (“H3K4me3”) determines when and how genes should be expressed.

It has been known for decades that the enzymes responsible for creating H3K4me3 (epigenetic “writers”) are essential for normal cell development. These enzymes, known as methyltransferases, are reversed by another class of enzymes, known as demethylases (epigenetic “erasers”). Demethylases specifically recognise H3K4me3 and remove this modification from chromatin. H3K4me3 is therefore constantly being created and erased from histone tails.

The scientists found that artificial loss of H3K4me3 leads to a significant increase of RNA polymerase II at the start of genes and increased pausing of RNA polymerase II in the middle of genes. RNA polymerase II is a large enzyme complex that reads DNA and transcribes the genetic information into RNA. In other words, RNA polymerase II is the mechanical driver of gene expression. The results of the study show that H3K4me3 is crucial in regulating the flow of RNA polymerase II, thereby determining when gene expression should occur and the speed at which it runs. Without H3K4me3, RNA polymerase II gets stuck at specific points along DNA, creating a “traffic jam” and slowing down gene expression.

Understanding how genes are activated at the right time can shed light on how cancer may develop. Increased expression of certain genes and reduced expression of others can contribute to runaway cell division, that is one of the hallmarks of cancer. Indeed, it is well established that the epigenetic status is widely altered during cancer progression. Previous studies have also suggested that disruption of H3K3me3 in particular is involved in cancer development and methyltransferase enzymes responsible for creating H3K4me3 are often found to be mutated in cancer.

This new breakthrough could therefore pave the way for a new class of cancer treatments that target epigenetic “traffic lights”, for example to repress genes involved in cancer, or to re-activate helpful genes that cancer cells learn to switch off. Drugs which target epigenetic “writers” and “readers” are also being developed to treat certain cancers. For example, small molecule inhibitors of histone methyltransferase enzymes, such as pinometastat and tazemetostat have been shown to display promising anti-tumour effects. Nevertheless, a major challenge faced by these drugs is that epigenetic events are distributed pervasively across the genomes of both healthy and cancerous cells. Therefore, approaches which can selectively target cancerous cells will likely be the focus of epigenetic-targeted therapies going forward.

It is clear that further developments in the exciting field of epigenetics will continue to expand our knowledge of the complex nature of gene regulation, and we expect to see more epigenetic-targeting therapeutics reaching the market in the near future.

J A Kemp attorneys, including Joanne Roberts, Karen Ng and Hiro Shimazaki have expertise in the field of epigenetics. Hiro’s Masters project focused on the role of ubiquitylation of histones in recruitment of histone variants. Karen’s PhD focused on the role of the non-coding RNA Xist in gene silencing in embryonic stem cells.