Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome

Cells package DNA into structures called chromosomes. When cells divide, each chromosome duplicates, and a structure called a centromere initially holds the copies together. The sequences of DNA on either side of the centromeres are often highly repetitive. In backboned animals, this DNA normally also has extra chemical modifications called methyl groups attached to it. The role that these methyl groups play in this region is not known, although in other DNA regions they often stop the DNA being ‘transcribed’ into molecules of RNA. The cells of people who have a rare human genetic disorder called ICF syndrome, lack the methyl groups near the centromere. The methyl groups may also be lost in old and cancerous cells. Researchers often use ‘model’ animals to investigate the effects of DNA modifications. But, until now, there were no animal models that lose methyl groups from the DNA around centromeres in the same way as seen in ICF syndrome. Rajshekar et al. have developed a new zebrafish model for ICF syndrome that loses the methyl groups around its centromeres over time. Studying the cells of these zebrafish showed that when the methyl groups are missing, the cell starts to transcribe the DNA sequences around the centromeres. The resulting RNA molecules appear to be mistaken by the cell for viral RNA. They activate immune sensors that normally detect RNA viruses, which triggers an immune response. The new zebrafish model can now be used in further studies to help researchers to understand the key features of ICF syndrome. Future work could also investigate whether the loss of methyl groups around the centromeres plays a role in other diseases where the immune system attacks healthy tissues.