Since almost every cell in the body contains the same genetic sequence, additional mechanisms are required to achieve tissue-specific gene expression and cell differentiation
. Thus, heritable biological factors that influence gene expression can be divided into two categories: the DNA sequence itself (the genome
) and other factors (the epigenome
One of the major molecular mechanisms by which information about gene activity is maintained and inherited is through the methylation
of cytosine bases in DNA. Usually, high levels of DNA methylation indicate that a gene is silenced, whilst active genes generally have lower levels of methylation. Unlike other epigenetic
mechanisms – such as modification of the histone proteins around which the DNA is coiled – DNA methylation is relatively stable and easily measurable. However, unlike genetic information which is (largely) immutable, epigenetic information can change dynamically over time and differs enormously between cells. Therefore decoding the human epigenome is proving to be a much more ambitious task than sequencing the genome (see previous news)
A team of American researchers has now provided the first map of the methylation state of every cytosine residue of the genome in two types of human cells, embryonic stem cells
and lung fibroblasts (connective tissue cells) [Lister, R. et al. Nature (2009) doi: 10.1038/nature08514
]. As expected, there were substantial differences in the location of DNA methylation in the two cell types. The surprise discovery was a significant difference in the type of cytosine residues that were methylated between the two cell lines. Like most adult cells, the fibroblast cells were predominantly methylated at so-called ‘CG sites’, where the cytosine is followed by a guanine base; in the stem cells, on the other hand, almost a quarter of the methylated cytosines were followed by a different base. Moreover, although standard CG-methylation is generally symmetrical (with both DNA strands being methylated), methylation in a non-CG context was almost always only present on only one strand. The authors hypothesize that this may be a general feature of human embryonic stem cells, which is necessary for maintaining pluripotency
and is lost upon differentiation.
Akin to the reference genome sequence, which has proved to be enormously important in genomics, the authors conclude that “these reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development”.