Epigenetics

The degree to which epigenetic mechanisms interest biologists currently may be judged by the fact that the prominent journal Cell recently devoted an entire special review issue to the subject (Cell, 128, February 23, 2007). In an introductory essay, Goldberg, Allis, and Bernstein offered several definitions of epigenetics. For the purpose of this discussion, they might be condensed as follows:

Further, the authors note that, "Much of today's epigenetic research is converging on the study of covalent and noncovalent modifications of DNA and histone proteins and the mechanisms by which such modifications influence overall chromatin structure." This is an awakening from a long fixation on DNA sequence to the realization that DNA exists in a cell as chromatin, a highly ordered and dynamic complex of DNA with histone proteins. Both DNA and histones are subject to chemical modification by enzymes. It is increasingly clear that the activities of these modifying enzymes can have very significant effects on the expression of genes, and that disruption of normal modification patterns can contribute to pathology in a wide range of diseases.

Epigenetic mechanisms seem to be particularly important for the establishment and maintenance of differentiated cell types during development. One of the most active areas of research considers the role of epigenetics in cancer. For example, epigenetic silencing of genes that normally suppress tumor development is now known to be an important factor in cancer development. More broadly, it seems likely that epigenetic mechanisms are key to the differences between totipotent embryonic stem cells, pluripotent progenitors, and committed cell types in specific lineages. Thus, understanding these mechanisms may be important in designing regenerative therapies.

Recent results suggest that histone acetyl transferases and histone deacetylases (HDACs) are key players in the regulation of the immune system and in some aspects of the biology of muscle, cartilage, bone, and skin. However, the functions of these enzymes are many and complex. It is not clear how often their activities actually lead to epigenetic phenomena, as opposed to more transient influences on gene expression. Nevertheless, because the class of drugs known as HDAC inhibitors has already been intensively studied, principally as potential cancer therapeutics, there is a chance that some insights into histone modification, whether truly epigenetic or not, could progress rapidly to clinical application.

Finally, recent technological advances in the rapid, comprehensive assessment of chromatin modifications open the way to mapping the "epigenome" in much the same way that genomic DNA sequences are now readily determined. This suggests that our understanding of epigenetics is likely to increase markedly in the next few years, yielding powerful new insights into mechanisms of disease and therapy.

Key questions

1. In which biological systems and diseases within the NIAMS mission are epigenetic mechanisms most important? What specific details have been learned to date? What are the crucial gaps in our understanding?
2. What are the key technologies currently available for investigating epigenetic mechanisms? What technical advances must occur in order to better understand the importance of epigenetic mechanisms in health and disease?
3. What are the potential approaches for exploiting insights into epigenetic mechanisms for therapeutic benefit? Which approaches are most promising for therapies involving stem/progenitor cells? For pharmacological treatment of systemic disorders?
4. What steps can the NIAMS take to advance the investigation of epigenetic mechanisms in skin, rheumatic, and musculoskeletal diseases? To facilitate the translation of biological information into diagnostic and therapeutic applications?

Background Materials

Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007 Feb 23;128(4):635-8.

Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007 Feb 23;128(4):669-81.

Callinan PA, Feinberg AP. The emerging science of epigenomics. Hum Mol Genet. 2006 Apr 15;15 Spec No 1:R95-101.