Epigenetics, Epigenomics, and Human Disease

The different cellular phenotypes that compose multicellular organisms are generated by the expression of housekeeping and celltype specific genes and repression of inappropriate ones. The pattern of gene expression that defines a celltype is termed the ‘epigenotype’ which is established and maintained by ‘epigenetic’ mechanisms able to govern gene expression regardless of the underlying genetic code. Genomic imprinting, where genes are expressed from only one of the inherited parental alleles, represents a classical example of epigenetic gene regulation; memory of the expression state, presumably established during gametic meiosis, is thus transmitted to the zygote, maintained throughout embryonic and postembryonic development, and reestablished during gametogenesis of the newly formed organism in a sex specific manner. It follows that epigenetic ‘plasticity’ would enable pluripotent stem cells to give rise to a variety of epigenotypes. Cells can acquire an epigenotype by modulating the availability of trans acting factors to regulatory cis acting genetic elements that specify gene activity or inactivity. Such availability can be controlled by the manner in which DNA is packaged as chromatin inside the nucleus. Silent genes may thus be packaged in ‘condensed’ chromatin such as heterochromatin. Conversely, active genes may be packaged in ‘open’ chromatin, termed euchromatin. It is clear that previously mysterious aspects of gene regulation that can be grouped under the term ‘epigenetic’ or ‘epigenomic’ are finally yielding to molecular biology approaches and have revealed a new level of genome organization and regulation. Already, the rapid increase in our understanding of the control of gene expression patterns has revealed potentially powerful new therapeutic avenues for an everincreasing number of human diseases, and a great variety of human cancers, many of which are currently incurable.