From Genome to Epigenome.......

Human Epigenome Project (HEP)

A vast code, invisible to the DNA sequencing effort that constituted the Human Genome Project, is rapidly being shown to play a direct role in human health.

Epigenetic modifications take several forms. The most intensively studied have been the addition of methyl groups, small "beads" of carbon and hydrogen, to DNA, which generally correlate with low gene activity. The histone proteins – molecular "clips" that hold the six feet of DNA tightly wound inside each cell - are modified by methylation, but also by the addition of chemical entities containing acetic acid, phosphorus, and a number of other species.(acetylation, phosphorylation)

Epigenetic modifications to DNA exert profound influences on gene activity. For example, studies suggest that epigenetic variation may be responsible for subtle differences in appearance and behavior of identical twins, whose gene activity profiles at 3 years of age are nearly alike, but by age 50 diverge as much as unrelated individuals in the population at large.

ROLE

Epigenetic aberrations also can play a role in normal and pathological processes, such as aging, mental health, and cancer, among others.

• An analysis of 25 brain tumors showed that a putative tumor suppressor gene was silenced by epigenetic mechanisms much more frequently than by genetic means.

• The bacterial species Helicobacter pylori, which has been widely linked to gastric cancer, was shown to induce epigenetic changes.

• Epigenetic marks also demonstrate diagnostic and predictive value. Of 148 human breast tumors included in one study, specific epigenetic modifications within the estrogen receptor gene correlated with greater chances of survival in response to tamoxifen.

APPROACH

Aim of the Human Epigenome Project (HEP) is to generate tissue-specific DNA methylation reference profiles of the human genome. The chosen approach involves treatment of the genomic DNA with sodium bisulphite which converts unmethylated cytosines into uracil but does not affect methylated cytosines. Following PCR amplification and sequencing of selected amplicons from bisulphite-converted DNA, the degree of methylation can be determined by comparison of the corresponding signal ratios at CpG dinucleotides, the predominant sites of DNA methylation.

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Changes to DNA sequence - the order of A, T, G and C in our genetic code - and their role in health and disease are increasingly well understood with the completion of the human genome sequence. But our cells use additional layers of gene control and DNA methylation is one of the most important regulators of gene activity. As well as being important for normal development, methylation changes are detected in many cancers and some developmental disorders such as Beckwith-Wiedemann syndrome.

Because DNA methylation is altered in many diseases and is associated with our response to medicines and other factors like aging, the HEP will provide a crucial link between genetics, the environment and health. Integration of genetic and epigenetic information will help us to understand how and when our genes are switched on or off and it will increase our ability to fight common and complex disease.