Mechanisms of epigenetic inheritance
What are the mechanisms of epigenetics responsible for?
Sergey Kiselyov, Post-science
Today, there is a lot of talk about such a direction as epigenetics (literally translated, it means "over-genetics"). Genetics – genes that are encoded in a DNA sequence, a genetic text. There is one and a half meters of such text in each human cell. These are letters that, when translated into letters known to us, will turn into multi-volume editions of the genetic text. But the genetic text consists of various combinations of four letters – nucleotides. These combinations encode the text of life.
Let's take for example the only cell from which the human body originates – a fertilized zygote. It will also contain these one and a half meters of genetic text. When a cell begins to divide, forming 2, 4, 6, 100 cells, the first specialization occurs. After this process, a whole organism is formed with all the variety of tissues – more than 200 different types of tissues. Each cell contains the same genetic text as the original one. The genetic text is the same, but some cells perform the function of blood, others – the function of skin, hair, intestines. The same text is embedded in each cell, but it is read differently in each one. Different reading of the genetic text by each cell is provided through the mechanisms of epigenetics. Despite the identical genetic text in each cell, the body is still able to live in different environmental conditions: first in the womb, then birth and elementary school, university, work. The body must adapt to each change. Epigenetic mechanisms are responsible for the ability of the body to adapt to external conditions.
The role of epigenetic mechanisms has become clearer, but the principle of operation has yet to be understood. We started with a genetic text that consists of four letters in various combinations. But we read words and combinations of words differently. For example, a familiar phrase from the famous cartoon "you cannot be pardoned", where the question of setting a comma arises all the time. The genetic text also has the same letters, but if you put a punctuation mark in one or another place, the meaning of the phrase will change.
Our genetic information is encoded by four letters: adenine, cytosine, guanine, thymine. These individual bases are nucleotides. One of the main epigenetic mechanisms that does not change the sequence of the genetic text, but puts a punctuation mark, is an additional methyl group based on cytosine. This mechanism does not change the base itself, but makes it cytosine and gives a certain intonation "punctuation mark". Today, DNA methylation under cytosine serves as the main tool in the study of epigenetic mechanisms and epigenetic features.
In this case, cytosine methylation can be controlled. There is a famous experiment that Randy Girtle put in the early 2000s on an agouti-colored mouse that had diabetes, obesity and had a tumor. Girtle began feeding the mouse with foods that contain more B vitamins and are rich in folic acids containing methyl groups. During the experiment, the mouse changed color and became white. Her obesity and diabetes disappeared, early tumor processes ceased to occur, and her offspring, who were also on this diet, also became white and fluffy.
"A study that showed that nutrition not only changes the work of DNA, but also causes transformations that are inherited, was conducted in 2003 at Duke University (USA). The objects for the experiment were the so-called agouti mice. They differ from ordinary mice by the activity of a special gene responsible for the formation of the agouti signal peptide. Under the influence of this protein, animals tend to become obese, the likelihood of developing tumors increases, and a pigment is formed in the hair follicles that gives the coat a yellow color (instead of brown or black). During the study, female agouti mice were "put" on a special diet shortly before mating: their diet was rich in folic acid, vitamin B12, as well as the amino acids choline and methionine. This style of eating persisted throughout the periods of pregnancy and lactation. Most of the cubs were born with normal coloring and healthy metabolic processes, without a tendency to obesity in adulthood. Moreover, children, grandchildren and several generations of mice born from the first offspring of agouti mice also had no signs of agouti peptide activity, although they adhered to a standard diet." (From the article "Epigenetics and Nutrition: what we eat will affect our descendants" – VM).
This effect appeared from an excess of methyl groups that were in the diet of mice. Methyl groups blocked the information part of the genome responsible for negative things in their ancestors: dirty yellow coat color, obesity and diabetes. Additional methyl groups triggered epigenetic mechanisms so that, without changing the sequence, but due to DNA methylation, the genes that were next to the negative site turned off. This is only one of the epigenetic mechanisms that, without changing the sequence of the genetic text, puts punctuation marks. Moreover, any changes of this type are supported by the cell and are inherited in a series of divisions. There are special methyltransferases – enzymes that use the DNA matrix to ensure DNA methylation in the next row of cell division. It is important to understand that such heredity in a number of cell divisions is not associated with a change in the original DNA sequence.
When a cell divides, the nucleus turns into two separate parts. The nucleus contains not just naked DNA, but chromosomes. Humans have 23 chromosomes. You also need to add a diploid set – a total of 46 turns out. Each cell inherits 46 chromosomes. A chromosome is a combination of DNA and proteins that pack our one and a half meters of DNA into each cell. The first level of compactification is nucleosomes, on which DNA is wound like a coil. Then these complex combinations fit into the following high-molecular structures. The location of DNA on nucleosomes is clearly inherited in every cell. The next epigenetic mechanism that ensures the transfer of memory to the daughter cell is the correct packaging of the DNA molecule on the nucleosome.
The protein bases that make up nucleosomes can also undergo chemical modifications without changing the nuclear structure. This property is important for epigenetic processes. Protein bases are highly susceptible to methylation and acetylation. If we have such a coil on which several turns of the DNA molecule thread are wound, then we can supplement the rollers and sides of this coil with some chemical bases. Such a hedgehog-shaped structure will make it difficult for other proteins to get to the DNA fragment that is wound on the coil. Other proteins will not be able to sit on the gene wound on this coil, it will be more difficult for it to work. If there are no such modifications, the sequence wound on the coil will be more accessible. If there are these modifications, they are less accessible, and the gene will be able to remain silent. This is the next level of mechanisms that are used to study epigenetics, inheritance unrelated to the DNA sequence. Our nucleic acid sequence can be methylated, and methyl groups can act as punctuation marks for genetic text. Also, the DNA molecule can be wound on nucleosomes, which undergo modifications and make it difficult or easier for other enzymes to access the genetic text. All these processes form a chromosome.
Today it is known that chromosomes exist in the nucleus in a distributed form. They do not exist in the form of clear worms, but in the form of chromosomal territory. Worms exist only during cell division. Each chromosome occupies its position in the cell, intertwining with the neighboring chromosome, and at the places of interweaving, the genes begin to work synchronously. The ability of genes to work synchronously at the level of chromosomal territories is also preserved in the process of division. This is the next mechanism that provides epigenetic inheritance. The sequence of the genetic text itself does not change, but the spatial arrangement of the fragments of the genetic text changes.
All these processes and mechanisms are examples of different levels of compactification. If necessary, without changing the genetic text "execute cannot be pardoned", put a comma, this is methylation. Then the nucleosomes are the final chapter in the book, which carries a separate meaning. And the chromosome territories are a collection of works that should be read in a specific sequence of volumes, one after the other. If you change the sequence of volumes, perception will be disrupted. If we read "War and Peace" not from the first volume, but start from the second, the sequence of the plot will be broken in our head. By analogy with the ordinary text, the genetic text is also read. In addition to letters, these are also punctuation marks, division into certain fragments and packaging into certain volumes, which must follow one after another or be located on a shelf next to each other so that the cell can perform its function and work correctly. This is inherited in a number of cell divisions.
About the author:
Sergey Kiselyov – Doctor of Biological Sciences, Professor, Head of the Epigenetics Laboratory of the N. I. Vavilov Institute of General Genetics of the Russian Academy of Sciences.
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