Researchers at Johns Hopkins have found that epigenetic marks on DNA-chemical marks other than the DNA sequence-do indeed change over a person's lifetime, and that the degree of change is similar among family members. Reporting in the June 25 issue of the Journal of the American Medical Association, the team suggests that overall genome health is heritable and that epigenetic changes occurring over one's lifetime may explain why disease susceptibility increases with age.
"We're beginning to see that epigenetics stands at the center of modern medicine because epigenetic changes, unlike DNA sequence which is the same in every cell, can occur as a result of dietary and other environmental exposure," says Andrew P. Feinberg, M.D., M.P.H, a professor of molecular biology and genetics and director of the Epigenetics Center at the Johns Hopkins School of Medicine. "Epigenetics might very well play a role in diseases like diabetes, autism and cancer."
If epigenetics does contribute to such diseases through interaction with environment or aging, says Feinberg, a person's epigenetic marks would change over time. So his team embarked on an international collaboration to see if that was true. They focused on methylation-one particular type of epigenetic mark, where chemical methyl groups are attached to DNA.
"Inappropriate methylation levels can contribute to disease-too much might turn necessary genes off, too little might turn genes on at the wrong time or in the wrong cell," says Vilmundur Gudnason, MD, PhD, professor of cardiovascular genetics at the University of Iceland director of the Icelandic Heart Association's Heart Preventive Clinic and Research Institute. "Methylation levels can vary subtly from one person to the next, so the best way to get a handle on significant changes is to study the same individuals over time."
The researchers used DNA samples collected from people involved in the AGES Reykjavik Study (formerly the Reykjavik Heart Study). Within the study, about 600 people provided DNA samples in 1991, and again between 2002 and 2005. Of these, the research team measured the total amount of DNA methylation in each of 111 samples and compared total methylation from DNA collected in 2002 to 2005 to that person's DNA collected in 1991.
They found that in almost one-third of individuals, methylation changed over that 11-year span, but not all in the same direction. Some individuals gained total methylation in their DNA, while others lost. "What we saw was a detectable change over time, which showed us proof of the principle that an individual's epigenetics does change with age," says M. Daniele Fallin, Ph.D., an associate professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health. "What we still didn't know was why or how, but we thought 'maybe this, too, is something that's heritable' and could explain why certain families are more susceptible to certain diseases."
The team then measured total methylation changes in a different set of DNA samples collected from Utah residents of northern and western European descent. These DNA samples were collected over a 16-year span from 126 individuals from two- and three-generation families.
Similar to the Icelandic population, the Utah family members also showed varied methylation changes over time. But they found that family members tended to have the same kind of change-if one individual lost methylation over time, they saw similar loss in other family members.
"We still haven't concretely figured out what this means for health and disease, but as an epidemiologist, I think this is very interesting, since epigenetic changes could be an important link between environment, aging and genetic risk for disease," Fallin says.
The research was funded by the National Institutes of Health, Swedish Cancer Foundation, Icelandic Parliament, Huntsman General Clinical Research Center, W. M. Keck Foundation, George S. and Delores Doré Eccles Foundation, Fulbright Foundation and the Icelandic Student Innovation Fund.
Authors on the paper are Hans Bjornsson, Martin Sigurdsson, Rafael Irizarry, Hengmi Cui, Wenqiang Yu, Michael Rongione, Fallin and Feinberg, all of Hopkins; Thor Aspelund, Gudny Eiriksdottir and Vilmundur Gudnason of Hjartavernd, Reykjavik, Iceland; Tomas Ekstrom of Karolinska Institute, Stockholm, Sweden; Tamara Harris and Lenore Launer of the National Institute on Aging, Bethesda, Md.; Mark Leppert of University of Utah, Salt Lake City; and Carmen Sapienza of Temple University Medical School, Philadelphia, Pa.