Epigenetics
terns of gene expression can be retained and passed on to descendents, evidence for how epigenetic memory occurs has been lacking. Understanding the mechanisms that promote cellular diversity using DNA sequences that are identical from cell to cell and how each contributes to epigenetic memo- ry will impact diverse areas of research, from agri- culture to human health and disease.
DNA methylation DNA methylation, the covalent addition of a Figure 1
Methylation-specific PCR of the p16 gene in two invasive carcinomas, a squamous intraepithelial lesion (SIL) and an adenocarcinoma of the
cervix. Results indicate that both invasive carcinomas and the SIL example contain methylated CpGs within a
region of the p16 CpG Island while the adenocarcinoma sample is free of methylation at the p16 locus
bacteria, protists, fungi, plants and animals, and rapid advances being made in the field is contribut- ing to our understanding of transcriptional regula- tion, nuclear organisation, embryonic development, ageing and disease.
Biologists have known for decades that epige- netics, particularly DNA methylation and chro- matin remodelling, is critical for the development of multi-cellular eukaryotic organisms, providing an explanation for how distinct cell types in the body develop in utero to fulfill a specialised func- tion despite each cell containing identical DNA. Each individual has only one genome but multiple epigenomes, which differ by cell and tissue type. Although the first epigenetic abnormality associat- ed with cancer was discovered in 19834, only recently has there been significant effort to identi- fy the role of epigenetics in the development of disease. This is because scientists now have advanced tools and technologies available for studying the epigenome in a relatively high- throughput fashion. They also realise that although it may take many generations for a genome to evolve, it takes only the addition of a methyl group to change an epigenome – and epigenomes change over the lifetime of an individ- ual. As a result, today epigenetic studies are com- plementing genetic approaches to the molecular basis of disease and providing insight into the age- old question: Can I control my fate?
Bypassing natural selection
Epigenetics has been described as the link between nature and nurture because epigenetic changes occur in response to environmental signals, includ- ing hormones, nutrients, stress and cellular damage (eg, smoking and sun exposure). There are three classes of epigenetic information that effect tran- scriptional and post-transcriptional regulation of genes: DNA methylation, chromatin associated protein post translational modification and certain non-coding RNAs that are associated with chro- matin. Although it has been confirmed that pat-
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methyl group (CH3) to the nucleotide cytosine, is involved in the regulation of many cellular process- es, including chromosome stability, chromatin structure, X chromosome inactivation, embryonic development and transcription. When a methyl group is added via DNA methyltransferases to the C-5 carbon of the DNA base cytosine, it projects into the major groove of the double helix and blocks transcription factors from binding to the promoter region of a gene. The addition of the methyl group can also serve as a docking station for proteins that bind to the methylated sequence and interact with additional protein modifiers of chro- matin structure. DNA methylation is maintained during cell division (and thus passed on to progeny) at dinucleotide C-G (CpG) via the enzyme DNA methyltransferase I. During DNA replication, DNA methyltransferase I seeks out hemi-methylated DNA and places a new methyl group on the daugh- ter CpG. Methionine, an essential amino acid, is the source of methyl groups in this reaction and is con- verted to a biologically active donor state through a pathway that involves folic acid.
Approximately 1% of the genome consists of 500-2,000 base pair CpG-rich areas, also known as CpG islands, and roughly 60% of all gene pro- moters include CpG islands. Most of the CpG islands with these promoters are unmethylated and thus actively transcribed5. One example of the importance of DNA methylation in altering the phenotype of an organism was demonstrated in 2003 with publication of the agouti mouse (Avy)6. If expressed continuously, the agouti gene gives mice yellow coats, they become obese in adulthood and are predisposed towards diabetes and cancer. Two groups of identical pregnant agouti mice were fed two different diets: one group received a diet rich in B vitamins (folic acid and vitamin B12) and the other group did not. The B vitamins acted as methyl donors, which caused methyl groups to attach much more frequently to the agouti gene in utero, thereby preventing its expression (in this case, a protective effect). As a result, the mothers who received B vitamins throughout pregnancy
Drug Discovery World Fall 2011
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