Free The Epigenetics Revolution by Nessa Carey Page B

these genes are active, the levels of methylation in the CpG island are low. The CpG islands tend to be highly methylated only when the genes are switched off. Different cell types express different genes, so unsurprisingly the patterns of CpG island methylation are also different across different cell types.
    For quite some time there was considerable debate about what this association meant. It was the old cause or effect debate. One interpretation was that DNA methylation was essentially a historical modification – genes were repressed by some unknown mechanism and then the DNA became methylated. In this model, DNA methylation was just a downstream consequence of gene repression. The other interpretation was that the CpG island became methylated, and it was this methylation that switched the gene off. In this model the epigenetic modification actually causes the change in gene expression. Although there is still the occasional argument about this among competing labs, the vast majority of scientists in this field now believe that the data generated in the quarter of a century since Adrian Bird’s paper are consistent with the second, causal model. Under most circumstances, methylation of the CpG island at the start of a gene turns that gene off.
    Adrian Bird went on to investigate how DNA methylation switches genes off. He showed that when DNA is methylated, it binds a protein called MeCP2 ( Me thyl C pG binding p rotein 2) 3 . However, this protein won’t bind to unmethylated CpG motifs, which is pretty amazing when we look back at Figure 4.1 and think how similar the methylated and unmethylated forms of cytosine really are. The enzymes that add the methyl group to DNA have been described as writers of the epigenetic code. MeCP2 doesn’t add any modifications to DNA. Its role is to enable the cell to interpret the modifications on a DNA region. MeCP2 is an example of a ‘reader’ of the epigenetic code.
    Once MeCP2 binds to 5-methylcytosine in a gene promoter it seems to do a number of things. It attracts other proteins that also help to switch the gene off 4 . It may also stop the DNA transcription machinery from binding to the gene promoter, and this prevents mRNA messenger molecule from being produced 5 . Where genes and their promoters are very heavily methylated, binding of MeCP2 seems to be part of a process where that region of a chromosome gets shut down almost permanently. The DNA becomes incredibly tightly coiled up and the gene transcription machinery can’t get access to the base-pairs to make mRNA copies.
    This is one of the reasons why DNA methylation is so important. Remember those 85 year old neurons in the brains of senior citizens? For over eight decades DNA methylation has kept certain regions of the genome incredibly tightly compacted and so the neuron has kept certain genes completely repressed. This is why our brain cells never produce haemoglobin, for example, or digestive enzymes.
    But what about the other situation, the example of skin stem cells dividing very frequently but always just creating new skin cells, rather than some other cell type such as bone? In this situation, the pattern of DNA methylation is passed from mother cell to daughter cells. When the two strands of the DNA double helix separate, each gets copied using the base-pairing principle, as we saw in Chapter 3 . Figure 4.2 illustrates what happens when this replication occurs in a region where the CpG is methylated on the C.

    Figure 4.2 This schematic shows how DNA methylation patterns can be preserved when DNA is replicated. The methyl group is represented by the black circle. Following separation of the parent DNA double helix in step 1, and replication of the DNA strands in step 2, the new strands are ‘checked’ by the DNA methyltransferase 1 (DNMT1) enzyme. DNMT1 can recognise that a methyl group at a cytosine motif on one strand of a DNA molecule is not matched on the newly synthesised strand. DNMT1 transfers a