DNA Methylation

Humans have 19,000 genes spread over 23 pairs of chromosomes and need all of those genes working in synchrony to make you—you. But not every cell needs to express every one of those genes. Your brain, for example, needs about a third of them to function properly. So what do the cells of your brain do with the other two thirds of the genes?

One option is to silence genes and regions of the genome not needed by adding a methyl group to them in a process called methylation. A methyl group is a tiny molecule composed of a carbon and three hydrogens. While small, the additive effect of many methyl groups can block the normal machinery of the cell from accessing the genome thereby effectively shutting the gene off. Methyl groups are added to DNA, but they can also be added to RNA or proteins.

The process is not merely about the turning on and off of genes, though. Methyl groups can also change the expression of the piece of DNA where they are added. More specifically, methylation turns the expression of that gene down, meaning that less protein will be made from the methylated gene as compared to an unmethylated copy of the same gene.

A hypermethylated gene may produce no protein, while a hypomethylated gene may produce a lot of the protein. This process can have dramatic effects on the appearance, physiology, behavior and functioning of the person.  This classifies methylation as a process that is not only fundamental to gene expression in the cell but also as a cornerstone of the modern study and understanding of epigenetics

One of the central questions in research currently is the role methylation plays as at the interface of gene expression and the environment. Data are mounting that the environment can influence the amount and placement of methyl groups on particular regions of the genome. For example, differences in methylation patterns are one reason why identical twins grow up to be two different individuals. The pattern of methyl groups on the DNA of a pair of three-year-old twins is almost identical to each other. But as the twins age, the patterns of methyl groups on their respective genomes begin to diverge due to the effects of their different environments–in turn changing their gene expression and subsequently their behavior, appearance, and physiology.

The role of methylation in the process of epigenetics has been known since the late 1970s/1980s. Through extensive research, we know that methyl groups are not just tagged randomly onto the DNA; rather, they are added primarily to cytosines – one of the four nucleotide bases that make up our genetic code (A, In order toC, G, and T). And not just any cytosine can be methylated–rather those that are located next to guanines (the G of the genetic code). This orientation is referred to as a “CpG island” (the “p” indicates a phosphates).

To understand how methyl groups decrease the expression of a gene, it is important to realize that CpG islands are frequently found near the promoter of a gene – the starting point for the expression of that gene. If the promoter has too many methyl groups attached to it, the transcription factors that begin the process of turning that gene into a protein cannot access the DNA–halting gene expression. As a result, very little or no protein will be made from that gene.

Methyl groups are not always permanent and can be added to or removed from DNA easily. Like many other processes in the cell, enzymes perform the addition and removal of methyl groups. The enzyme that adds methyl groups to DNA is called a DNA methyltransferase (DNMT). A demethylase removes methyl groups from DNA.

We each have two copies of almost every gene in our cells – one on each chromosome. However, for some genes, expression from only one copy is needed–in fact, expressing both copies can often be dangerous to the cell. Therefore, the second copy of the gene must be shut down. The way cells silence the second copy of the gene is by adding methyl groups in a process known as “genomic imprinting.” If the imprinting process is not functioning correctly, a disease may result. In contrast, if too much methylation is occurring in the cell, a disease can also occur. For example, Fragile X syndrome, the most common cause of inherited mental disabilities in males, is a result of too much methylation at the promoter of the FMR-1gene.

For most organisms, methylation is a normal process in the cell and an important part of regulating gene expression. A methylated cytosine is so common in the human genome that it is often referred to as the 5th base.

The process of DNA methylation varies widely between species or, even kingdom. The model organisms Caenorhabditis elegans (nematode worm) and Saccharomyces cerevisiae (yeast) have no methylated DNA whereas the DNA of plants is heavily methylated.