NAS Holds Workshop on Use of Emerging Science and Technologies to Explore Epigenetic Mechanisms Underlying the Developmental Basis for Disease

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NAS Holds Workshop on Use of Emerging Science and Technologies to Explore Epigenetic Mechanisms Underlying the Developmental Basis for Disease

Published: September 18, 2009
The NAS held a workshop on July 30-31 to evaluate the state of the science of epigenetics, with particular attention to understanding whether it is a significant contributor to a number of human diseases. Epigenetics refers to changes that occur in gene expression that are not attributable to changes in DNA sequence. This is different than mutation, which does involve changes in the genetic code that are permanent. The best known epigenetic changes are those that occur during development; while each cell contains the same complement of DNA, genes become silenced as cells become differentiated. This allows cells to express only the characteristics of the tissue type in which they are located. The silencing of expression of genes unrelated to the function of each differentiated cell type explains why most cells cannot become stem cells, even though they contain the same genes as stem cells.

The molecular mechanisms for epigenetic changes involve either the direct modification of DNA by methylation, or the acetylation of the histone proteins that are associated with DNA. Methylation is at specific sites and in specific sequences of nucleotides. Modification of DNA or DNA-associated proteins in this way prevents the DNA from being transcribed. Epigenetic silencing is generally life-long and in some instances can be transmitted to the next generation.

In addition to the normal developmental programming that occurs as cells differentiate, epigenetic changes can occur during development in response to certain maternal nutritional conditions. Maternal undernutrition during pregnancy can result in persistent changes in metabolism in her offspring. Perhaps the most well known example of this is the epidemic of obesity in the children of women who were pregnant during the famine in Holland that occurred at the end of World War II. Epigenetic mechanisms may also be at play in the etiology of some adult diseases that are of developmental origin. This notion has been called the Barker hypothesis. It stems from observations that low birth weight (apparently attributable to maternal nutritional status) predisposes men to a higher incidence of hypertension, cardiovascular disease and metabolic disease in middle age. Newer evidence indicates that epigenetic changes are important in some forms of cancer, and there are even some therapies that rely on manipulation of epigenetics.

While it is clear that epigenetics are an important developmental mechanism, there are many uncertainties about the extent to which epigenetic changes are responsible for diseases, or even which epigenetic mechanisms are susceptible to environmental influences. This lack of information makes it difficult for regulatory agencies to make decisions about how to evaluate the potential for chemicals and drugs to cause disease by epigenetic mechanisms. There was much discussion at the workshop about whether existing animal studies are indirectly testing for epigenetic effects, and on how to screen large numbers of chemicals for epigenetic effects. The most promising alternative methods would use stem cells, as these undergo epigenetic changes as they differentiate. However, the details on setting up such assays, let alone their interpretation, remain to be worked out.