Epigenetic modifications and human disease (original) (raw)

1057 generated from the same donor DNA are not identical to, and develop diseases with different penetrance from, their donor 1,3. Human clones that arise spontaneously—monozygotic twins—are identical at the DNA sequence level, but have different DNA methylation 4,5 and his-tone modification profiles 4 that might affect the penetrance of several diseases, such as cancer 4 or autoimmune disorders 6. But this phenomenon is also observed at a single cell level: how can stem cells develop into any type of cell and how does a liver cell always give rise to two new liver cells after cell division? Again, epigenetics seems to be part of the answer as it has been described as one of the key factors in cellular differentiation 7,8 (see the review by Meissner 9 in this issue). The importance of epigenetics in maintaining normal development and biology is reflected by the observation that many diseases develop when the wrong type of epigenetic marks are introduced or are added at the wrong time or at the wrong place 10. For instance, a clear causality role for DNA methylation in cancer is suggested by hypermethylation of some genes (e.g., p16 INK4a , p14 ARF and MGMT) as an early event in tumorigenesis, as well as by tumor type-specific methylation landscape 11. Here we summarize recent progress in the field of epigenetic research and its role in disease, preparing ourselves for the surprises that epigenetics might hold in the future. Epigenetic modifications and their machineries For didactic purposes, epigenetic modifications can be grouped into three main categories: DNA methylation, histone modifications and nucleosome positioning. It is important to keep in mind the interplay between epige-netic factors—as the observed outcome is always the sum of their interac-tions—and the many positive and negative feedback mechanisms. DNA methylation. The most widely studied epigenetic modification in humans is cytosine methylation. DNA methylation occurs almost exclusively in the context of CpG dinucleotides. The CpG dinucleotides tend to cluster in regions called CpG islands 1 , defined as regions of

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