International Business Department           Liu Bojia           September 18, 2024

  DNA methylation has been intensively studied in the field of epigenetics over the past four decades, and its changes have been closely associated with many human diseases (especially cancer) as well as aging.

  DNA methylation, a chemical modification that occurs on the DNA molecule, mainly involves the addition of a methyl group to the carbon atom at position 5 of cytosine (C) to become 5-methylcytosine (5mC). This stable epigenetic mark, together with epigenetic marks occurring on histones (e.g. acetylation modifications), acts as an ‘on/off switch’ to control gene expression, thus ensuring that thousands of genes are activated or silenced at the right time and in the right place in the cell.

  Not long ago, researchers at the Institute of Molecular Biology (IMB) in Mainz, Germany, discovered a new DNA epigenetic marker in vertebrate cells: 5-formylcytosine (5fC), following DNA methylation. According to the team's paper, published in the leading academic journal Cell, the newly discovered epigenetic modification also acts as an ‘on/off switch’ to activate gene expression, regulating it during early embryonic development.

  According to a press release from the Institute, this discovery is significant and represents a true breakthrough in the field of epigenetics, demonstrating that vertebrates have more than one type of DNA epigenetic markers and revealing previously unknown mechanisms of epigenetic gene regulation. And it will be interesting to see what role this new epigenetic modification plays in human diseases such as cancer.

  In this study, Professor Christof Niehrs led a team that first looked at the timing of the appearance of 5fC in embryos of the African clawed toad. Using microscopy and chromatography, they observed a rapid increase in 5fC during an early stage of embryonic development called ‘syncytial genome activation’. Conjugal genome activation is the first transcriptional stage after the onset of life, when many genes are switched on and large amounts of conjugal RNA begin to be produced, and it is during this short, critical phase that chromocenters of 5fC are formed in the cell.

  These 5fC chromocenters are located in the so-called perinucleolar compartment, a subnucleosome connected to the nucleolus, and contain RNA polymerase III, which is involved in DNA transcription. further observations showed that during the syncytial genome activation phase in Xenopus laevis, the target genes of RNA polymerase III are highly enriched in 5fC when they are activated. 5fC. Therefore, the researchers hypothesised that 5fc may play an important gene regulatory role in early embryonic development.

  In subsequent experiments, the study authors genetically manipulated two enzymes that act on cytosine in order to regulate the amount of 5fC on DNA, and found that increasing 5fC led to an increase in gene expression, whereas decreasing the amount of 5fC decreased gene expression, suggesting that the presence of this DNA epigenetic marker can activate genes.

  After demonstrating in Xenopus laevis that the 5fC modification of DNA acts as an epigenetic switch to initiate genes during early embryonic development, this study went further to observe in mouse embryos that the process of syncytial gene activation also has 5fC chromocentres.

  The researchers note that several chemical modifications of DNA other than methylation have also been identified in vertebrates over the past decade, but all were present in very small amounts and it was uncertain whether they were functional epigenetic marks. In contrast, the 5fC identified in this new study is likely to have a role in activating gene expression in vertebrates, including mammals.

  Moreover, in addition to regulating early development, what role this DNA epigenetic modification might play in disease has also attracted the attention of researchers. Previous studies have found that a large proportion of cancer cells in the metastatic stage have perinuclear compartment structures. Cancer cells may contain large amounts of 5fC, and whether 5fC modifications can be targeted to reverse disrupted gene regulation will require more subsequent studies to answer.