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It Is Time for a Human Epigenome Project

In this issue, Peter Jones, Robert Martienssen, and colleagues (1) make a very strong case for initiating a large-scale, international Human Epigenome Project (HEP). The AACR and the National Cancer Institute have taken the lead in this field by bringing together experts in the diverse fields of epigenetics and epigenomics in the form of Think Tanks and the recent comprehensive AACR-sponsored Workshop focused on planning the HEP. Emanating from this Workshop is a clear set of needs, guidelines, and expectations of the HEP and the conclusion that it has the potential to influence almost every facet of human biology and disease research.

The sequence of the human genome has provided the first hardwired blueprint for human genetic diversity. Further transcript annotation, multiple comparative genomic projects, large-scale polymorphism studies, and the Cancer Genome Project will continue to refine the hardwired variation we each inherit and catalog somatic mutation which causes and predisposes to human disease. However, it is now clear that this level of complexity pales in comparison to the epigenetic constraints imposed on our genome during development, homeostasis, and disease initiation and progression.

From the information encoded by the DNA we each inherit, individual, tissue-specific, and disease-specific epigenomes with unique gene expression patterns are created by covalent modification of the DNA and by post-translational modifications to the histones that package the DNA. Like genetic information, epigenetically encoded information is stable and both mitotically and meiotically heritable. This has led to the remarkable paradigm that the "unit" of heritability is not simply the hardwired DNA sequence of a gene, but the gene plus its covalent modifications and the modifications to the chromatin that package the gene.

The enzymology required for placing and maintaining epigenetic marks, such as methylation of DNA and acetylation, methylation, and phosphorylation of histones, is rapidly becoming defined. It is also clear that there are direct interplay and cross-talk between DNA and histone modification, the sum of which defines an epigenetic code at specific genes that determines expression levels. The HEP seeks to define these epigenetic marks at high resolution in the genome, define their interplay and interdependence, and determine how non-random alterations to the epigenetic code occur during disease.

A key point is that unlike the hardwired information encoded in DNA, epigenetic marks are reversible and highly dynamic. Modulation of these marks directly affects gene activity and cellular phenotype. Thus, pharmacologic manipulation of the epigenome by targeting the enzymes which place and maintain these marks is highly feasible and has already been shown to be therapeutically efficacious in cancer and other diseases. These results are particularly relevant at a time when there is intense pressure on scientists to translate discoveries obtained from expensive "big science" projects to direct patient benefit. 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. Defining cancer epigenomes will aid in selecting patients who are likely to benefit from epigenomic therapies and prevention strategies, help in determining its efficacy and specificity, and lead to the identification of surrogate markers and end points for its effects. Therapies using the epigenome as a target have the capacity to deliver on the promise of genomic/molecular medicine.

The Workshop also effectively addressed strategic issues that a HEP will face, including: Is the technology ready? Who will coordinate the effort? What model systems, if any, should be used? What is the role of the public and private sectors?

With the experience and rhetoric of the early days of planning for the human genome project still ringing in our ears, it is clear that none of these issues are insurmountable and, in fact, have provided a roadmap of how to leverage the international assets available for the HEP.

In summary, it is time to create a concerted international effort to unlock the epigenomic information stored in our genome and use it for the benefit of human health.

References

1. Jones PA, Martienssen R. A Blueprint for a Human Epigenome Project: The AACR Human Epigenome Workshop. Cancer Res 2005;24:11241–11246.

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