With a $5 million, five-year federal grant, The Johns Hopkins University School of Medicine is establishing what is believed to be the first university-based research center devoted to studying epigenetics, an effort that will set the stage for learning as much about our epigenetics as the Human Genome Project taught about the sequence of building blocks that make up our genes.
Much as our genetic sequence is passed from parent to child, epigenetic "marks" that sit on our genes are also inherited. These "marks," usually small methyl groups, are attached to genes' backbones and convey information, such as identifying which parent the gene came from. The marks also normally turn genes on or off. But just as changes in genes' sequences can cause diseases such as cancer, gain or loss of epigenetic marks can, too, by improperly turning genes on or off.
"Epigenetics may be as important in certain conditions, or in contributing to the risk of developing certain conditions, as the genetic sequence is in other cases," says Andrew Feinberg, M.D., King Fahd Professor of Medicine and principal investigator of the epigenetics grant. "Epigenetics doesn't underlie all human disease, but we definitely need to develop the technology to figure out when and where epigenetic changes do influence health and disease."
Feinberg, who pioneered the study of epigenetics in cancer, will lead the new Center for the Epigenetics of Common Human Disease at Johns Hopkins, which is funded by the National Human Genome Research Institute and the National Institute of Mental Health. Through the center's grant, Feinberg and his colleagues will first develop tools to create comprehensive information about epigenetics and then apply that information to the study of autism and bipolar disorder. The epigenetic information and technologies will also be available to researchers investigating other conditions.
"Having the human DNA sequence is just the first step in our quest to understand the complexities of the biological systems in the human body. Epigenetic effects undoubtedly play an important biological role, and learning more about these effects is essential to deciphering the mysteries of human health and disease. So, we are thrilled that Johns Hopkins has pulled together this world‑class team of researchers to move this important field forward," says NHGRI Director Francis S. Collins, M.D., Ph.D.
The ambitious Hopkins center is the ninth grant funded through the NHGRI's and NIMH's Center for Excellence in Genome Science program, and the first to focus on epigenetics.
"This center reflects a trend at Hopkins to shift toward interdisciplinary research, really pulling together those working on related problems, regardless of their department affiliations, to tackle important basic questions whose answers will advance human health," says Chi Dang, M.D., Ph.D., vice dean for research at the Johns Hopkins School of Medicine. He adds that Hopkins' Institute for Cell Engineering and the Institute for Basic Biomedical Sciences are both advancing such multidisciplinary research models.
Given its own "multidisciplinary" status, the center will be bigger than Feinberg's laboratory alone. Among the key players are 15 other researchers from Hopkins and elsewhere whose work and collaborations will be critical to the center's success.
"As we studied epigenetics in cancer, it became clear that we needed to 'genomicize' epigenetics, to really investigate the issue more broadly than simply its role in cancer," says Feinberg. "This center is a first, critically important step toward creating a comprehensive picture of epigenetics and its role in human health."
First on the center researchers' to-do list is development of technology to speed identification of epigenetic marks and their locations in the genome and then adapt these methods to examine multiple sections of the genome and many samples at once.
Next, with Johns Hopkins colleagues and collaborators from a German company called Epigenomics, the Icelandic Heart Foundation and Pennsylvania State University, these new technologies will be used to examine the entire epigenomes of specific groups of people to hunt for clues to human disease. The first groups to be analyzed will be families -- at least a "trio" of parents and child -- from two Johns Hopkins groups studying the genetic bases of autism and bipolar disorder, and from the 30-year effort of the Icelandic Heart Foundation.
"Iceland isn't much different from Northern Europe in terms of its genetic diversity, but organizations like the Icelandic Heart Foundation boast great documentation of familial relationships, medical histories and thorough and quantitative medical examination to go along with blood and tissue samples," says Feinberg. "There is great scientific value in what they have and what they do."
In particular, Feinberg points out that researchers at the IHF invented high-throughput, quantitative phenotyping -- the ability to rapidly assess the biologic traits and characteristics that stem from genetic, epigenetic and environmental influences. With the IHF information and samples, Feinberg and his colleagues will determine whether and how epigenetic marks shift over time and how a child's epigenetic marks differ from his or her parents'.
"The genetic sequence is essentially fixed for life, but we believe epigenetic marks are more subject to change," says Feinberg. "The IHF collaboration will let us really test the stability of epigenetics and the passage of those marks from parents to child, perhaps even over successive generations."
At the heart of the center's work is epigenetics' importance in proper cell function and in development. One example of epigenetics is "imprinted" genes -- genes whose activity is determined not by the regular dominant and recessive rules of Mendel's genetics, but solely by which parent provided the gene copy. For example, for some imprinted genes only the copy from the mother is used, while for other imprinted genes, only the copy inherited from the father is turned on. (Our cells contain two copies of every gene, one from the mother and one from the father.)
At some point before, during or after egg meets sperm, epigenetic marks such as those used for imprinting must be reset and re-established, so that a gene passed from father to daughter to son is appropriately marked, for example. Knowing how and when this happens, and whether the process can be controlled, has important implications for understanding human development and the viability of animals and stem cells created through somatic cell nuclear transfer, a process colloquially known as "cloning."
As part of the center, Feinberg and his colleagues will also implement a "minority action plan" to encourage racial and ethnic minorities to pursue education and careers in genetics and genomics. The plan offers select local students the chance to conduct genetics and genomics research during their summer breaks, and Feinberg will work with staff at the Center for Talented Youth (CTY), a Johns Hopkins endeavor with sites across the country, to add a genomics component to the program's summer classes. Starting in 2005, the Epigenetics Center will fund four minority students each year to attend these classes.
"The idea is to groom an interest in science and in genomics from a young age, hopefully increasing the number of minorities who pursue education and careers in genome sciences," says Feinberg.
Others closely involved with the center's work are Karl Broman and Margaret Fallin, Johns Hopkins Bloomberg School of Public Health; James Potash, Hengmi Cui, Patrick Onyango, J. Raymond DePaulo, Hans Bjornsson, David Nichols and Jef Boeke of the Johns Hopkins School of Medicine; Kurt Berlin, Epigenomics AG; Vilmundur Gudnason, Icelandic Heart Foundation; Webb Miller, Pennsylvania State University; Eric Green, NHGRI; Tamara Harris, National Institute on Aging; and Lea Ybarra, The Johns Hopkins University, Center for Talented Youth. Nichols and Ybarra will be principally involved with the center's minority action plan. Feinberg is also a member of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins.