INTRODUCTION
The term ‘epigenetics’ was first introduced by Conrad Waddington in the 1940s to describe ‘the interactions of genes with their environment, which bring the phenotype into being’ (1
). The ensuing research on gene regulation during cell differentiation and development has raised most of the questions that are still at the core of epigenetics. Early epigenetic studies described heterochromatin as regions of the genome that have low gene density, contain satellite repeat elements and are late replicating. Subsequently, it was shown that heterochromatin and euchromatin are associated with distinct DNA methylation and histone modification patterns that correlate with particular states of gene activity, leading to the idea of an ‘epigenetic code’ that determines the chromatin state and, consequently, gene expression (2,3). More recently, an epigenetic memory system mediated by polycomb (pcG) and trithorax group (trxG) proteins to maintain silent chromatin states has been uncovered (4,5), and short hairpin RNAs have been shown to play a role in heterochromatin formation via an RNAi pathway (6,7), placing heterochromatin at the core of epigenetic silencing. Heritable variations in gene expression, such as gene silencing due to paramutation in plants, X-inactivation in mammals and genomic imprinting, have highlighted the complexity of gene regulation, so that nowadays epigenetics is simply defined as heritable changes in gene expression not attributable to nucleotide sequence variation.
Following the trend from local to global analyses, the term epigenomics was introduced for the study of epigenetic changes on a genome-wide basis (8). Fundamentally, epigenomics is the study of the effects of chromatin structure including the higher order of chromatin folding and attachment to the nuclear matrix, packaging of DNA around nucleosomes, covalent modifications of histone tails (acetylation, methylation, phosphorylation, ubiquitination) and DNA methylation. These epigenetic components are all amenable to genome-wide study, and integrated studies that correlate gene expression with DNA methylation and chromatin profiles need to be designed. However, it will be of limited value to study the epigenome in a generic cell. Traditional genomic resources such as cell lines undergo expression and methylation changes in culture, whereas primary tissues are often made up of numerous cell types. Moreover, epigenetic changes can also occur as a result of external factors such as age and diet. Thus, serious consideration needs to be given to origins of cell type as well as the developmental stage. Various tissues of diseased and healthy origin will need to be studied, and as a baseline, epigenetic profiles need to be established in ‘normal’ tissues.
The enormous interest in epigenetics has encouraged several groups to exploit whole genome approaches to embark upon characterizing the epigenome. Dedicated academic centres to study epigenetics are being formed in various universities, the largest being the Center for the Epigenetics of Common Human Disease at Johns Hopkins (http://www.hopkinsmedicine.org/epigenetics/). In Europe, two major international consortia of similar name but different and complementary aims have been formed. The Human Epigenome Project (HEP) (www.epigenome.org) is a joint effort by an international collaboration, which was established in 1999 with the aim to identify, catalogue and interpret genome-wide DNA methylation patterns and profiles of all human genes in all major tissues. The Epigenome Network of Excellence (www.epigenome-noe.net) was established in 2004 with the aim to provide a portal to a vast array of epigenetics resources and information for both the scientists and the interested public and to advance epigenetic research (for human and model organisms) into chromatin modification, nucleosome dynamics, non-coding RNA and gene silencing, X-chromosome inactivation and imprinting, transcriptional memory, assembly and nuclear organization, cell fate and disease and epigenomic maps.
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