A vast code, invisible to the DNA sequencing effort that constituted the Human Genome Project, is rapidly being shown to play a direct role in human health. This “epigenome”--from the Greek epi, meaning “in addition to”--consists of chemical “amendments” that dangle like charms on a bracelet from the linear string of letters that spell out the genetic code.
Now, an international group of 40 leading cancer scientists says the time is ripe to undertake a large-scale international “Human Epigenome Project” designed to map the chemical modifications to DNA that comprise the epigenetic code. Their proposal, “A Blueprint for a Human Epigenome Project”--published in the December 15, 2005 issue of Cancer Research--summarizes the findings of an American Association for Cancer Research-sponsored workshop held June 15-18, 2005, in Lansdowne, Virginia.
“Definition of the human epigenome and its application to developing diagnostic, prognostic and therapeutic tools will likely produce some of the earliest translational research benefits flowing from large-scale genome initiatives to the bedside,” said Frank Rauscher, III, Ph.D., editor-in-chief of Cancer Research.
The new report spells out the needs, guidelines and expectations of a Human Epigenome Project (HEP), and describes the developing technologies that make the project currently feasible.
“One of the most exciting points to emerge from the meeting is that the technology needed for doing epigenetics on a high-throughput basis has advanced so far that people are already engaged in epigenomic studies on a piecemeal basis,” said Peter A. Jones, Ph.D., D. Sc., president of the AACR and Director of the Norris Comprehensive Cancer Center at the University of Southern California. Jones and Robert Martienssen, Ph.D., a professor at Cold Spring Harbor Laboratory, New York ( firstname.lastname@example.org , tel: 516-367-8322) were co-organizers of the workshop.
Epigenetic modifications to DNA exert profound influences on gene activity. For example, studies suggest that epigenetic variation may be responsible for subtle differences in appearance and behavior of identical twins, whose gene activity profiles at 3 years of age are nearly alike, but by age 50 diverge as much as unrelated individuals in the population at large.
Epigenetic aberrations also can play a role in normal and pathological processes, such as aging, mental health, and cancer, among others. Several presenters at the workshop highlighted significant contributions that epigenetic phenomena make to a broad spectrum of human cancers. For example:
---An analysis of 25 brain tumors showed that a putative tumor suppressor gene was silenced by epigenetic mechanisms much more frequently than by genetic means.
---The bacterial species Helicobacter pylori, which has been widely linked to gastric cancer, was shown to induce epigenetic changes.
---Epigenetic marks also demonstrate diagnostic and predictive value. Of 148 human breast tumors included in one study, specific epigenetic modifications within the estrogen receptor gene correlated with greater chances of survival in response to tamoxifen.
---Presence of a distinct epigenetic modification in 140 examined neuroblastoma cases correlated with a poor prognosis, and other marks were linked to colon cancer progression.
Epigenetic modifications take several forms. The most intensively studied have been the addition of methyl groups, small “beads” of carbon and hydrogen, to DNA, which generally correlate with low gene activity. The histone proteins--molecular “clips” that hold the six feet of DNA tightly wound inside each cell--are modified by methylation, but also by the addition of chemical entities containing acetic acid, phosphorus, and a number of other species.
The complex nature of epigenetic modifications constitutes a challenge to the development of reliable, high-throughput methods of cataloging them. Several workshop participants, however, working in both industrial and academic settings, have developed techniques proving adept at tackling epigenetic complexity.
These include the so-called ChIP/chip methodology, in which intact chromatin--the complex of DNA and histones--is immunoprecipitated (brought out of solution using antibodies that recognize specific histone modifications) and analyzed on microarray “chips.” Modifications of DNA are also tracked on chips, following treatment with enzymes that recognize sites of methylation. Impressive accounts of success with these methods were presented at the workshop.
These accounts included a report from the European Epigenome Project, headquartered at the Wellcome Trust Sanger Institute in Cambridge, England, which has completed a pilot phase and expects to analyze 10 percent of the genome by fall 2006.
The proposed structure of a Human Epigenome Project takes into account that “there is not one epigenome,” according to the authors, “but rather many different epigenomes.” Epigenetic profiles differ among tissues, individuals and healthy vs. disease states. Workshop participants advocate choosing a small number of “reference” epigenomes to be analyzed at a high level of resolution. Tissues proposed for this analysis include peripheral blood cells and foreskin fibroblasts.
Participants agreed that a much larger group of samples could be examined using a lower-resolution “scanning” approach that would help delineate basic principles of epigenetic effects on gene activity. The scanning approach would point out areas that should be “drilled down” with additional study.
As stated by the authors: “The goal of the HEP is to identify all the chemical changes and relationships… that provide function to the DNA code, which will allow a fuller understanding of normal development, aging, abnormal gene control in cancer and other diseases, as well as the role of the environment in human health.”
Jones, Martienssen and the other workshop participants call for any U.S. effort to coordinate closely with those in other countries, including additional European projects underway as well as efforts in Japan, where an active epigenetic research community exists.
The workshop, sponsored by AACR, was also attended by representatives of the National Cancer Institute, which sponsored a related workshop on epigenomics in December 2004 and another one last month defining the epigenome.
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