Randy L. Jirtle, PhD: epigenetics a window on gene dysregulation, disease. Interview by Bridget M. Kuehn.

SCIENTISTS STUDYING ONE FACET OF how gene activity is orchestrated may be starting to unravel the mystery of how genes interact with the environment to cause disease. They have found that many of these changes are epigenetic in nature. Epigenetic changes may be thought of as chemical switches that can turn on and off the expression of genes in response to environmental factors. Randy L. Jirtle, PhD, of Duke University Medical Center in Durham, NC, explained that epigenetic changes may allow species to adapt rapidly in response to environmental signals early in life. But some epigenetic changes can increase risk of disease if they lead to dysregulation of genes or if there is a mismatch between the environment during development and the environment encountered in adulthood. While the field of epigenetics is still in its infancy, scientists have already compiled compelling evidence for the role of epigenetics in cancer, and animal studies are providing provocative evidence that nutritional factors and other exposures at the earliest stages of development cause epigenetic changes that can increase the risk of disease later on (Jirtle RL and Skinner MK. Nat Rev Genet. 2007;8[4]:253-262). JAMA: What is epigenetics? Dr Jirtle: Epigenetics changes are heritable changes that alter the expression of the gene without changing the DNA sequence. Epigenetic programming involves chemical changes, such as the addition or removal of methyl groups from DNA or histones that alter whether certain genes are expressed. By epigenetically varying the repertoire of the genes expressed in cells, a single genome can result in the formation of liver cells, skin cells, neurons, and other cell types that have completely different functions. JAMA: When are these changes likely to occur? Dr Jirtle: Epigenetic changes occur most commonly during gestation, neonatal development, puberty, and old age. The epigenome is most vulnerable, however, to environmentally induced alterations during embryogenesis, when DNA synthesis is rapid and the DNA methylation patterning and chromatin structure required for normal development is established. Once established, these epigenetic alterations are faithfully passed on to the daughter cells during somatic cell division. If these epigenetic changes are not completely erased during gametogenesis, they can potentially affect health not only in the present, but also for future generations. JAMA: What have animal studies been able to tell us about the role of epigenetics in disease? Dr Jirtle: Our studies using the yellow agouti strain of mice have shown that the mother’s nutrition during pregnancy can permanently change the epigenetic programming of her offspring (Waterland RA and Jirtle RL. Mol Cell Biol. 2003;23[15]:5293-5300). JAMA: Are there limits to what these types of animal studies can tell us about epigenetics? Dr Jirtle: Epigenetic programming varies greatly between species. For example, we recently developed computer learning algorithms that predicted the presence of 600 imprinted genes in mice (Luedi PP et al. Genome Res. 2007;15[6]:875-884) and 156 imprinted genes in humans (Luedi PP et al. Genome Res. 2007;17[12]:17231730). Humans are predicted to have fewer imprinted genes than mice, and there is also only a 30% overlap between their imprinted gene repertoires. The divergence of imprinted genes between mice and humans indicates the need to identify the regulatory elements of imprinting in humans if we are to understand the role these genes play in the etiology of human diseases and neurological disorders. JAMA: How has epigenetics been implicated in human disease? Dr Jirtle: The role that epigenetics plays in cancer has been most clearly demonstrated. There are a number of tumor suppressor genes known to be inactivated epigenetically in human tumors (Baylin SB. Nat Clin Pract Oncol. 2005;2[suppl 1]:S4-S11). Imprinted oncogenes (eg, IGF2) are also frequently overexpressed in human cancers because of loss of