New Chapter in Epigenetics

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

Immunofluorescence shows C. elegans eggs: DNA in blue and a previously unreported DNA modification where adenines are methylated in red. Image: David Aristizábal-Corrales

Immunofluorescence shows C. elegans eggs: DNA in blue and a previously unreported DNA modification where adenines are methylated in red. Image: David Aristizábal-Corrales

Scientists have discovered a new position for a DNA modification that could carry heritable epigenetic information. Video: Elizabeth Cooney

We are more than the DNA sequences we inherit from our parents.

Nongenetic information is also passed from one generation to the next, the burgeoning field of epigenetics tells us. If parents or grandparents live with some altered state of health that is not the direct result of their genetic code, their descendants may experience that condition to some degree themselves, as if they bear some ancestral memory.

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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. They report their results in Cell.

Immunofluorescence shows C. elegans eggs: DNA in blue and a previously unreported DNA modification where adenines are methylated in red. Image: David Aristizábal-Corrales

Over the past 20 years, a growing body of evidence has implicated chemical marks that are added to the DNA letters A, G, T and C that represent the bases adenine, guanine, thymine and cytosine. Chemical additions such as a methyl group are attached to the letters on the double-helix strand and thereby influence the way genes produce proteins.

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.

More to the story

Shi’s team is revising the epigenetics story once again. 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.

Modifications such as these are important because they work together to control cell function, Shi said.

'A new angle'

“This is important not only for C. elegans. Now we have a new angle to look at the possible role DNA adenine methylation may play in transmitting epigenetic information,” Shi said.

Epigenetic modifications give the DNA code a blueprint, saying one region of the genome should produce proteins in one cell type and another region should not.

DNA works as a prime carrier of epigenetic information. When the double-stranded helix splits in two, the parental strand acts as a template for the sequence as well as for the modifications in the newly synthesized daughter strand. This system helps propagate epigenetic marks to the next generation DNA strand.

To test whether the A methylation they discovered in C. elegans could play a role in epigenetic inheritance, Greer and Blanco engineered the worms to carry a mutation of an enzyme involved in methylation that over subsequent generations would make them less fertile.

They found correlation of increased A methylation with the epigenetic inheritance of the declining fertility phenotype, though not ironclad cause and effect. They confirmed this with a series of proteomic and sequencing tools not available in the dawn of the epigenetic era.

Shi said the Cell paper represents one more piece of the epigenetic puzzle.

“We have one genome but we have many epigenomes. Every cell has a slightly different variation of the genome that allows it to express a very specific set of genes,” Shi said, which is especially clear in stem cells that give rise to muscle or liver or brain cells. “Studies from the past two decades collectively point to the possibility that we’re not just inheriting DNA sequences alone, but something else in addition.”

This work was supported by a Helen Hay Whitney postdoctoral fellowship, a National Institute on Aging of the National Institutes of Health grant (K99AG043550), an NIH NRSA postdoctoral fellowship (1F32CA180450-01), a Special Fellow award from the Leukemia & Lymphoma Society (3353-15) the Intramural Research Program of the National Library of Health, NIH, and U.S. Department of Health and Human Services, NIH grants (GM058012, CA118487, and K99AG043550), an Ellison Foundation Senior Scholar Award and a Samuel Waxman Cancer Research Foundation grant. Other collaborators of this study include postdoctoral fellows Lei Gu, Erdem Sendinc, David Aristizábal-Corrales and Chih-Hung Hsu from the Shi lab, L. Aravind from the National Institutes of Health, and Jianzhao Liu and Chuan He of the University of Chicago.