Epigenetic Switch Found to Activate Genes in Embryos

Researchers led by the Institute of Molecular Biology have found that 5-formylcytosine (5fC), a DNA alteration, acts as an activating epigenetic switch to activate genes during the early stages of embryonic development. This discovery clarifies how genes are controlled during the earliest phases of development and establishes for the first time that vertebrates possess multiple types of epigenetic DNA marks. The journal Cell published their study.

Trillions of cells make up human bodies, and they all cooperate to produce a living, breathing entity. However, every human began as a solitary fertilized egg cell. This one cell has to divide quickly to produce all the organs in the right locations and grow into a whole human being. Precisely, the timing and location of thousands of genes' activations are essential to this developmental process.

Epigenetic modifications linked to DNA and its corresponding proteins turn genes on or off, and they function like on-or-off switches.

For many years, scientists believed that the single epigenetic change in DNA found in vertebrates, known as cytosine methylation and linked to gene silence, existed alone in these animals. Ten years ago, three other chemical alterations were found in vertebrate DNA, but because they were so minute, researchers were not sure if they were functioning epigenetic markers.

For the first time, researchers led by Professor Christof Niehrs have demonstrated the role of 5-formylcytosine, one of these changes, in early development gene activation. The finding is noteworthy because it reveals a novel, hitherto unidentified mechanism of epigenetic gene control and establishes that vertebrates possess multiple types of epigenetic DNA marks.

These findings are a real breakthrough in epigenetics because 5fC is only the second proven epigenetic DNA modification besides methylcytosine.”

Christof Niehrs, Founding and Scientific Director, Johannes Gutenberg University Mainz

The scientists examined 5fC in frog embryos in their investigation. They found that 5fC rises sharply during the beginning of development during a crucial stage known as zygotic activation, when numerous genes become active, using microscopy and chromatography.

The observation of 5fC in microscopically visible tiny dots, or chromocenters, was exciting. Based on them, we suspected that 5fC must do something important in early embryonic development.”

Eleftheria Parasyraki, Study First Author, Johannes Gutenberg University Mainz

To demonstrate that 5fC is an activating epigenetic mark, the researchers genetically altered the embryo's enzymes to change the DNA's 5fC content. It was evident that the presence of 5fC on the DNA activates genes since increasing 5fC led to increased gene expression, and decreasing 5fC led to decreased gene expression.

Lastly, during the activation of zygotic genes in mouse embryos, the researchers also noticed 5fC chromocenters. This implied that in both mammals and frogs, 5fC probably functions as an activating epigenetic mark.

The finding that 5fC is an activating epigenetic regulator on DNA raises many issues about its precise mechanism of action and its function beyond early zygotic genome activation. 5fC levels can be quite high in cancer cells. More research on 5fC will be required to address these issues and perhaps further our understanding of how diseases alter gene regulation and human development.