Cytosine bases here and there in DNA are famously decorated with methyl groups, chemical modifications that silence genes so that specific cells express only certain, appropriate DNA sequences. This safety strategy ensures, for instance, that eyelash cells don’t sprout from spleen cells.
Thanks to new research, cytosines can no longer claim to be the only bases that slip on a methyl group in mammals. Adenine bases can also be methylated, says Yale University’s Andrew Z. Xiao, whose research team found the modification in mouse stem cells. Xiao and his team recently identified an enzyme responsible for removing the chemical mark from adenine (Nature 2016, DOI: 10.1038/nature17640).
Although adenine methylation has long been observed in single-celled organisms, researchers didn’t think it decorated the DNA of multicellular organisms, comments Gerd P. Pfeifer, who studies epigenetics at the Van Andel Research Institute in Grand Rapids, Mich. “Adenine methylation in DNA was totally ignored for a very long time,” Pfeifer says. By 2015, the epigenetic mark had been reported in algae, plants, mosquitoes, fruit flies, and worms—discoveries in multicellular organisms that tantalized researchers with the possibility that mammalian DNA may also possess the mark. Last December, researchers at the University of Cambridge reported initial evidence suggesting the epigenetic mark was also found in adult human and mouse cells (Nature Struct. Mol. Biol. 2015, DOI: 10.1038/nsmb.3145).
Methylated adenine appears to be quite rare in mammalian cells, Xiao says. For example, DNA in mouse stem cells has about six to seven methylations per million adenine bases, a frequency several orders of magnitude rarer than cystosine methylation.
To find the mark in mouse stem cells, Xiao’s team carefully measured the kinetics of polymerase enzymes as they replicated DNA during sequencing. The rate of the replication slowed when the enzymes hit a methylated adenine. The team then used mass spectrometry to confirm the presence of the mark at these spots on the DNA.
In the new study, Xiao and colleagues also took a stab at figuring out what role the epigenetic mark plays. They found that, like methylated cytosines, methylated adenines silence genes in mouse stem cells, albeit using an entirely independent system of enzymes.
Curiously, research in worms and flies suggests adenine methylation is involved in activating nearby genes, a function opposite to what Xiao’s group found in mouse stem cells. “I’ve spent a lot of time trying to figure out this difference,” he says. “We need to do a lot more research before we can connect all the dots.”