Unsuspected DNA modification raises possibility of new carrier of heritable epigenetic information

Scientists don’t know the exact molecular nature of the epigenetic information that one generation transmits to the next. The list of candidate carriers includes proteins, noncoding RNA and the histones around which DNA winds itself. Or it could be modifications to the DNA itself that somehow get replicated when cells divide.

Now, a Harvard Medical School team has written a new chapter in the epigenetics story, with their discovery of a new position for an epigenetic modification to DNA that potentially carries heritable epigenetic information.

Over the past 20 years, a growing body of evidence has implicated chemical marks that are added to the DNA.  The best studied modifications scientists have found occur when a methyl group marks the C. More ancient organisms have other modifications, including methylation of the A.

Yang Shi, HMS professor of cell biology, overturned dogma in the field in 2004 when he showed that methylation of histones is not static. Adding a methyl group to histones—the spool around which the DNA double helix wraps to form chromosomes—can help turn a gene on or off; so does removing a methyl group. The discovery of enzymes that specifically remove methyl groups highlights the dynamic nature of histone methylation regulation, a process that is critical for stem cell biology, development and differentiation, and when it goes awry, can lead to many human diseases. Their surprising discovery was made in C. elegans, a transparent roundworm that is a widely studied model organism.

Scientists previously thought that C. elegans simply had no DNA methylation because their C letters showed no signs of the methyl modification that other animals have. It is also unknown how they can transmit epigenetic modifications across generations.

Shi’s team reports that C. elegans does in fact carry DNA methylation, but not on the C position. They found epigenetic modifications to adenine at the same location previously thought to exist only in more primitive organisms.

They also identified the enzymes that act to methylate and demethylate the A. Further bolstering their case, they showed that a transgenerational epigenetic inheritance system in C. elegans, which displays a generationally progressive reduced fertility, also progressively accumulates A methylations.

“We have identified what we think is a fundamental new layer of regulation that occurs in animals,” said Eric Greer, formerly a postdoctoral fellow in the Shi lab and now HMS assistant professor of pediatrics at Boston Children’s Hospital. “We’re excited about this because this is a modification that hasn’t previously been shown to occur in Metazoa, of which humans and worms are members.”

The more common C modification may overshadow the A modification in more recently evolved animals, said co-lead author Andres Blanco, an HMS postdoctoral fellow in pediatrics in the Shi lab.

“Maybe it’s not the dominant form of DNA methylation, but maybe it has a smaller role that is nonetheless extremely important,” he said. Harvard Medical School