Epigenetic mechanisms in human disease.

If one accesses the human genome websites, either the publicly or privately funded, and examines the information, one will find only the four letters A, G, T, and C in various combinations. However, one will not find a fifth letter we know to exist, namely C for 5-methylcytosine. For cancer research, this is a significant issue as alterations in DNA methylation in human cancer were first discovered in 1983 (1), and since that time, hundreds of labs have examined epigenetic alterations in human tumors and their role both in the activation of tumor promoter genes as well as silencing of tumor suppressor genes. Although epigenetic modifications are not shown in the databases, a clue within those databases to the importance of epigenetics comes from the comparison of the published human and mouse sequences. This analysis reveals that 1.5% of the conserved sequences in both genomes represent the coding sequences of genes, but another 1.5% of the genome represents conserved noncoding elements that may be within introns or at a considerable distance from the genes themselves. For the most part, these sequences are GC-rich and therefore potential targets of methylation. Furthermore, we are only beginning to understand sequences involved in epigenetic regulation of gene expression. Indeed, most of our efforts that have identified the molecular basis of disease have been focused upon the genes themselves rather than upon these regulatory sequences. It should therefore be no surprise that epigenetic mechanisms are found to play a role in many human diseases, including cancer, but also that epigenetic mechanisms lie at the very heart of our understanding of stem cell therapy, animal cloning, complex traits, and aging. After all, what is the difference between a somatic cell and an early embryonic cell other than epigenetic, given that their genomes are the same, but their function and developmental potential are quite different and yet stably inherited as the cells divide. An intensive two-day conference sponsored by the Center for Cancer Research of the National Cancer Institute in Bethesda, Maryland, brought together an outstanding group of investigators from eight countries studying epigenetic mechanisms in development and disease. To our knowledge, it was the first such conference that addressed epigenetic mechanisms of human disease generally, not only cancer, and the proceedings are available in their entirety on line.