DNA methylation

DNA methylation is a fascinating biological process where methyl groups are added to DNA. This doesn’t change the DNA sequence, but it can turn genes on or off. When methylation happens in a special part of a gene called a gene promoter, it usually stops that gene from being active, a process known as repressing gene transcription.

In animals, DNA methylation is very important for normal growth. It helps with processes like genomic imprinting, where certain genes act differently depending on whether they come from the mother or the father, and X-chromosome inactivation, which ensures that females, who have two X chromosomes, use only one of them in each cell. It also helps control jumping pieces of DNA called transposable elements, plays a role in aging, and is linked to carcinogenesis, or the development of cancer.

Scientists have found that DNA methylation mainly happens on two types of building blocks, or nucleobases, in DNA: adenine and cytosine. Cytosine methylation is common in many living things, from plants to animals, though the amount can vary a lot between species. This process is important for keeping DNA stable and accurate as it copies itself.

Conserved function of DNA methylation

DNA methylation is a process where small chemical groups are added to DNA, which can change how genes work without changing the DNA sequence itself. In animals, most DNA is usually methylated, but in plants and other organisms, the pattern is more mixed.

One important role of DNA methylation is to keep certain genes turned off. It can also stop pieces of DNA called "transposable elements" from moving around, which helps keep the genome stable. In highly active genes, methylation can also help with reading the gene correctly.

In mammals

DNA methylation patterns change a lot between generations in mammals. Most of the methylations from parents are removed twice — first during the formation of eggs and sperm, and again early in the development of the embryo. This removal happens in two steps in very early embryos. After this, a new wave of methylation happens when the embryo implants in the mother, which helps control which genes are active in different cells. These patterns stay the same for a long time, helping each cell type stay unique.

DNA methylation helps keep certain genes turned off, especially in cells that have finished developing. It is very important for keeping genes quiet in a way that depends on which parent the gene came from, and for turning off one of the two X chromosomes in females. Without DNA methylation, many specialized cells cannot survive. However, in early stem cells, DNA methylation is not needed.

DNA methyltransferases (in mammals)

DNA methylation in mammals mainly happens at a specific spot in DNA called CpG dinucleotides. There are two main types of enzymes that add methyl groups to DNA: those that maintain existing methylation patterns and those that create new ones.

One enzyme, DNMT1, helps keep methylation patterns the same when cells copy their DNA. Another group of enzymes, including DNMT3A and DNMT3B, sets up new methylation patterns early in development. There are also special proteins that help these enzymes work better.

In plants

We have learned a lot about DNA methylation using a small plant called Arabidopsis thaliana. In plants, DNA methylation works a bit differently than in animals. While animals mostly add methyl groups to a specific part of the DNA called a CpG site, plants can add them to several different places.

Scientists have identified enzymes in plants, such as DRM2, MET1, and CMT3, that add these methyl groups to DNA. These enzymes help control which genes are active and which are turned off, playing a role in protecting the plant’s DNA from harmful changes caused by viruses and other elements. Different plants have different levels of DNA methylation, with some having much more than others.

In insects

Further information: Epigenetics in insects

Insects show different levels of DNA methylation. For example, butterflies have low levels, while true bugs and some cockroaches have higher levels, up to 14% of certain DNA sites. In honey bees, DNA methylation helps regulate genes, mainly marking the gene body.

Fruit flies, known as Drosophila melanogaster, have very low levels of DNA methylation, around 0.1–0.3% of total cytosine. Recent studies show even smaller amounts of another type of methylation during early development stages.

In fungi

Many fungi have small amounts of a special change called DNA methylation, which can affect how genes work. The amount of this change varies between different types of fungi. Some fungi have very little, while others have more.

Some tiny fungi, like brewers' yeast and fission yeast, do not have DNA methylation at all. However, a type of fungus called Neurospora crassa does have a system for DNA methylation. Scientists study this fungus to learn more about how DNA methylation works, because changing the genes that control this process does not stop the fungus from growing or reproducing.

In other eukaryotes

DNA methylation is rarely found in Dictyostelium discoideum, occurring in only about 0.006% of cytosines. However, it is much more common in Physarum polycephalum, where 5-methylcytosine can make up to 8% of all cytosines. This shows that DNA methylation varies greatly between different organisms.

In bacteria

Adenine or cytosine methylation in bacteria is managed by special systems that help protect the bacteria from viruses. These systems use enzymes called methylases to add methyl groups to specific parts of the DNA. This marking helps the bacteria recognize their own DNA and destroy foreign DNA from invaders like bacteriophages.

In E. coli, a specific enzyme called DNA adenine methyltransferase (Dam) adds methyl groups to a sequence called GATC. This process is important for fixing mistakes in DNA, controlling when DNA copies itself, and turning genes on or off. The methylation helps the cell know which part of the DNA is the original and which is the new copy. Without proper methylation, bacteria can make more mistakes in their DNA. Certain genes, like those for making hair-like structures called pili, depend on this methylation to turn on or off based on the bacteria's environment.

Detection

DNA methylation can be found using many different scientific methods. One common way is Mass spectrometry, which can detect methylation but does not tell us where in the DNA it is located. Another method is Methylation-Specific PCR (MSP), which uses a special chemical to change unmethylated parts of DNA, making it easy to see if a section is methylated or not.

Other techniques include Whole genome bisulfite sequencing, which looks at the entire genome after treating DNA with a chemical that changes unmethylated parts. There are also methods like Enzymatic methyl-seq (EM-seq), which uses enzymes to find unmethylated areas, and the HELP assay, which uses special enzymes that can tell if DNA is methylated. Scientists also use Pyrosequencing and Illumina Methylation Assay to measure methylation levels accurately. These tools help researchers understand how DNA methylation affects genes and health.

Differentially methylated regions (DMRs)

Differentially methylated regions (DMRs) are parts of DNA that have different patterns of methylation in different samples, such as tissues or cells. These regions can help control which genes are active, playing a role in gene regulation. For example, certain DMRs can help scientists identify specific body fluids, which is useful in forensic science.

There are different types of DMRs, such as those found between cancer and normal cells, or those that change during development or with age. Researchers use tools like QDMR to measure and identify these regions across many samples, helping to understand how DNA methylation affects health and disease.

DNA methylation marks

DNA methylation marks are special patterns of chemical tags added to DNA in different cells and tissues. These patterns help control which genes are active, influencing how cells behave and what they can do. Scientists study these patterns to understand how cells develop and stay specialized.

DNA methylation is also useful for identifying tiny amounts of body fluids, like blood or saliva, from crime scenes or medical tests. By looking at methylation patterns, researchers can tell what kind of fluid is present, even in very small samples. This method works well even when the samples are old or damaged, making it a powerful tool for solving crimes and monitoring diseases like cancer.

Computational prediction

DNA methylation can be studied using computer programs and special methods. These programs help scientists understand where methylation happens across entire chromosomes. They are often quicker and more affordable than experiments done in a lab. Some of these modern methods are from researchers like Bhasin, Bock, and Zheng. Using both computer models and lab experiments helps scientists learn more about DNA methylation.