Scientists Discover New Epigenetic Switch

Researchers have discovered that a DNA modification called 5-formylcytosine (5fC) acts as an activating epigenetic switch that triggers genes in early embryonic development. This discovery shows that vertebrates have more than one type of epigenetic DNA mark and sheds new light on the regulation of genes in the earliest stages of development. The results were published in the journal Cell.

5fC is Only the Second Epigenetic DNA Modification to be Detected, Alongside Methylcytosine

Our bodies are made up of trillions of cells that all work together to form a functioning organism. Each of us began as a single fertilized egg cell. To become a complete human being, this single cell must multiply rapidly and form all the right organs in the right places. This developmental process depends on thousands of genes being activated at exactly the right time and in the right place. The activation/deactivation of genes is controlled by so-called epigenetic modifications, i.e., chemical groups that are bound to the DNA and the associated proteins and act like traffic lights to switch the genes on or off.

For decades, scientists believed that vertebrates had only one type of epigenetic modification of DNA, called cytosine methylation, which is associated with gene silencing. Ten years ago, three additional chemical modifications were discovered in vertebrate DNA, but because they occurred in very low levels, scientists were unsure whether they were functional epigenetic marks. Professor Christof Niehrs and his team have now shown for the first time that one of these modifications, 5-formylcytosine, is involved in gene activation in early development. The discovery is significant because it proves that vertebrates have more than one type of epigenetic DNA mark and reveals a new, previously unknown mechanism of epigenetic gene regulation. In development

5fC Plays an Important Role in Early Embryonic Development

“These results are a real breakthrough in epigenetics, as 5fC is only the second proven epigenetic DNA modification after methylcytosine,” says Niehrs, founder and scientific director of the IMB, which opened on the campus of Johannes Gutenberg University Mainz (JGU) in 2011. In their study, the scientists investigated 5fC in frog embryos. Using microscopy and chromatography, they discovered that 5fC increases dramatically at the beginning of development during a crucial step called zygotic activation, when many genes are switched on. Eleftheria Parasyraki, first author of the study, explains: “The observation of 5fC in microscopically visible tiny dots, the chromocenters, was exciting. Based on this observation, we suspected that 5fC must play an important role in early embryonic development.”

To prove that 5fC is an activating epigenetic marker, the scientists genetically manipulated enzymes in the embryo to increase or decrease the amount of 5fC on the DNA. An increase in 5fC led to increased gene expression, while a decrease in 5fC reduced gene expression, suggesting that the presence of 5fC on the DNA actually activates the genes. Finally, the scientists also observed 5fC centromeres in mouse embryos during zygotic gene activation.

This suggests that 5fC likely functions as an activating epigenetic marker in both mammals and frogs. The discovery that 5fC is an activating epigenetic regulator on DNA raises many questions about how exactly it works and what role it plays beyond early zygotic genome activation. In particular, cancer cells can express very high levels of 5fC. To answer these questions, further investigation of 5fC is needed, which could ultimately help us better understand how we develop and how gene regulation is disrupted in disease.