The information to make the cells of all living organisms is contained in their DNA. DNA is made from 4 bases abbreviated as G, A, T, and C, and is built like a very long ladder with pairs of these letter making up each of the "rungs" of the ladder. The letter G pairs with C and A with T. Strings of these pairs store information like a coded message, with the information to make specific molecules grouped into regions called genes. Every cell in our bodies contains two copies of every one of our genes, with one copy of each gene coming from our mother and one copy from our father. (The only exceptions to this rule are genes on chromosomes that determine whether we develop as a male or a female.)
Not every gene should be expressed in every cell of our bodies. For example, we do not want our brain cells to make hemoglobin, the protein required to carry oxygen around in our blood. Only those cells that will ultimately make red blood cells should make hemoglobin. If brain cells contain an intact copy (in fact 2 copies) of the gene for the hemoglobin protein, why don't brain cells also make hemoglobin? In fact, the level of the intermediate in hemoglobin protein production (this intermediate is a short copy of the hemoglobin gene called RNA), is at least a million times lower in brain cells than in the cells that are in the process of turning into red blood cells. Hence, there must be processes that control what gene is turned on, or expressed, in each cell type and these processes can produce differences in activity of at least a million fold. These controlling processes actually determine what type of cell it is, for example whether it is a red blood cell, a brain cell, a muscle cell, or a skin cell!

To regulate the level at which any gene is expressed, there are complex sets of regulatory proteins that bind to parts of the DNA encoding each gene. In very complex organisms such as ourselves, many control factors have to be acting together to achieve the levels of power and refinement of gene regulation needed. One of these levels of control is provided by adding a small "tag" called a methyl group onto C, one of the bases that make up the DNA code. The methyl group tagged C's can be written as mC. Simpler organisms, such as many types of bacteria and the single-celled yeast, usually do not use methyl group tagged C's in regulating their genes. Some bacteria, but not all, use methyl group tagged A's (mA) for this purpose. However, most bacteria have specific patterns of mC and mA in their DNA as a signal that says "this is my DNA", and acts as part of an immunity mechanism that allows these cells to destroy the DNA from infecting viruses without destroying their own DNA.

Methyl group tags in the DNA of humans and other mammals play an important role in determining whether some genes are or are not expressed. Genes unnecessary for any given cell's function can be tagged with the methyl groups. The number and placement of the methyl tags provides a signal saying that the gene should not be expressed. There are proteins in the cell which specifically recognize and bind the tagged C's, preventing expression of the gene. In addition, some of these proteins provide an important signal determining just how tightly folded that section of the DNA becomes. Folding up the long thin DNA molecules in our cells is not a trivial problem. If all of the DNA present in each of our tiny cells was stretched out in a line, it would be almost 3 meters (10 feet) long! Hence, the DNA must be folded up and compacted. How the DNA is compacted plays an important role in determining which genes can be used. In general, genes in tightly compressed DNA are not well expressed, while genes in more loosely packed DNA are more available to the machinery involved in copying the gene into the intermediate for expression, RNA.

As would be expected from something important in determining which genes are used by our cells, DNA methylation is essential for the normal development and functioning of organisms. This has been shown by engineering mice that can't make the enzymes which put the methyl tags on DNA, called methyltransferases. These mice die before birth. Problems with the DNA methylation machinery also cause developmental diseases in people. People with mutations causing abnormal function of one of the DNA methyltransferase enzymes called Dnmt3b have a disease called ICF syndrome. These people have abnormal immune systems and other genetic problems. Similarly, abnormalities in one of the proteins recognizing and binding mC (called MeCP2) develop Rett syndrome, a form of mental retardation affecting young girls. Hence, we cannot develop and function normally without DNA methylation.

Abnormal DNA methylation plays an important role in other developmental diseases as well. With most genes, it probably does not matter that both copies of the gene (the one from the mother plus the one from the father) are both active. However, with a few genes, only one copy is normally active. This could be the copy from the mother or the father, and the one which is active is specific for that particular gene. Imprinting is the term used when the expression of a gene depends on whether it is inherited from the mother or the father. Imprinting "breaks" one of Mendel's laws that genes act the same whether transmitted by either parent. Imprinting was first discovered in corn: kernels are dark purple if the Red gene is inherited from the egg but blotchy lavender if the same gene is transmitted through the pollen. This observation was made in 1910. Today we know that in the pollen (which contains the plant sperm cells) the Red gene is methylated and only slowly during kernel development are the methyl tags removed, permitting gene expression. In humans, some babies are born with abnormalities due to both copies of imprinted genes being active. This has been shown to be due to a failure in the establishment of the normal pattern of methyl group tags that blocks the activity of one of the copies of the gene. Diseases caused by this type of methylation problem include Prader-Willi syndrome, Angelman's syndrome and Beckwith-Wiedemann syndrome.

Abnormal placement of the DNA methylation tags also develops with aging. The tags can decrease in number in some genes, and increase in others, causing inappropriate decreases or increases in the activity of the genes affected. The changes in the placement of the methyl tags may be responsible for a variety of changes in cellular function that occur during aging. There is also evidence that abnormal placement of the methyl tags may contribute to the development of human lupus.

Very frequent abnormal increases or decreases in DNA methylation tags are found in most human cancers and contribute to their development. If the genes affected by abnormal methylation tagging happen to be involved in regulating cell proliferation, uncontrolled cell division can occur, and this uncontrolled cell growth is the problem underlying cancer. Scientists are trying to change the abnormal tags or the effects of these tags as one treatment for cancer and to use these tagging differences in early diagnosis of cancer and in monitoring various treatments of cancer. Additional practical aspects of studying DNA methylation are its importance in determining whether some types of bacteria are capable of causing disease; how plant crops develop, diversify, and can be improved; and the formation of birth defects associated with in vitro fertilization in people and cloning in animals. Of particular importance in flowering plants, methylation is part of the host plant defence against the movement of small invading DNA molecules that can jump from chromosome to chromosome, called transposons. A similar process happens in animals, where methylation is part of the defence against viruses that have incorporated their genes into the host's DNA.

Understanding the many complex roles of DNA methylation is a very active field of research involving laboratories throughout the world. The DNA Methylation Society is an association formed by scientists interested in the many different aspects of this area of fundamental and applied research.