Epigenetic mechanisms. Epigenetics: theoretical aspects and practical implications. Epigenetic effects in humans

Perhaps the most capacious and at the same time precise definition of epigenetics belongs to the outstanding English biologist, Nobel laureate Peter Medawar: "Genetics suggests, but epigenetics disposes."

Did you know that our cells have memory? They remember not only what you usually eat for breakfast, but also what your mom and grandmother ate during pregnancy. Your cells remember well whether you play sports and how often you drink alcohol. The cell memory stores your encounters with viruses and how much you were loved as a child. Cellular memory decides whether you will be prone to obesity and depression. Largely due to cellular memory, we are not like chimpanzees, although we have approximately the same genome composition with it. And this amazing feature of our cells has helped to understand the science of epigenetics.

Epigenetics is a fairly young direction of modern science, and so far it is not as widely known as its "sister" genetics. Translated from Greek, the preposition “epi” means “above”, “above”, “above”. If genetics studies the processes that lead to changes in our genes, in DNA, then epigenetics studies changes in gene activity, in which the structure of DNA remains the same. One can imagine that a certain “commander” in response to external stimuli such as nutrition, emotional stress, physical activity, gives orders to our genes to increase or, conversely, to weaken their activity.

Mutation management

The development of epigenetics as a separate branch of molecular biology began in the 1940s. Then the English geneticist Konrad Waddington formulated the concept of "epigenetic landscape", explaining the process of the formation of an organism. For a long time it was believed that epigenetic transformations are characteristic only for the initial stage of the development of the organism and are not observed in adulthood. However, in recent years, a whole series of experimental evidence has been obtained that produced the effect of a bomb exploding in biology and genetics.

A revolution in the genetic worldview took place at the very end of the last century. A number of experimental data were obtained in several laboratories at once, which made geneticists think hard. For example, in 1998, Swiss researchers led by Renato Paro from the University of Basel conducted experiments with Drosophila flies, which, due to mutations, had yellow eyes. It was found that under the influence of an increase in temperature in mutant fruit flies, offspring were born not with yellow, but with red (as is normal) eyes. They activated one chromosomal element, which changed the color of the eyes.

To the surprise of the researchers, the offspring of these flies retained their red eyes for another four generations, although they were no longer exposed to heat. That is, the acquired traits were inherited. Scientists were forced to draw a sensational conclusion: stress-induced epigenetic changes that did not affect the genome itself can be fixed and passed on to the next generation.

But maybe this only happens in fruit flies? Not only. Later it turned out that in humans, the influence of epigenetic mechanisms also plays a very important role. For example, it has been found that the predisposition of adults to type 2 diabetes can largely depend on the month of their birth. And this despite the fact that between the influence of certain factors associated with the season, and the onset of the disease itself, 50-60 years pass. This is a good example of the so-called epigenetic programming.

What can link the predisposition to diabetes and the date of birth? New Zealand scientists Peter Gluckman and Mark Hanson were able to formulate a logical explanation for this paradox. They proposed the "mismatch hypothesis", according to which a developing organism can undergo "prognostic" adaptation to the environment expected after birth. If the prognosis is confirmed, it increases the organism's chances of survival in the world in which it will live. If not, adaptation becomes maladjustment, that is, a disease.

For example, if during intrauterine development the fetus receives an insufficient amount of food, metabolic changes occur in it, aimed at storing food resources for future use, "for a rainy day." If there is really little food after birth, it helps the body to survive. If the world that a person enters into after birth turns out to be more prosperous than predicted, this “thrifty” nature of metabolism can lead to obesity and type 2 diabetes in the later stages of life.

The experiments carried out in 2003 by American scientists from Duke University Randy Girtl and Robert Waterland have already become textbooks. A few years earlier, Jirtl had managed to insert an artificial gene into ordinary mice, which made them born yellow, fat and sickly. Having created such mice, Girtl and his colleagues decided to test: is it possible, without removing the defective gene, to make them normal? It turned out that it was possible: they added folic acid, vitamin B 12, choline and methionine to the food of pregnant agouti mice (as they began to call yellow mouse "monsters"), and as a result of this, normal offspring appeared. Nutritional factors have been shown to be able to neutralize mutations in genes. Moreover, the effect of the diet persisted in several subsequent generations: baby agouti mice, born normal thanks to food additives, themselves gave birth to normal mice, although their diet was already normal.

We can confidently say that the period of pregnancy and the first months of life is the most important in the life of all mammals, including humans. As the German neuroscientist Peter Spork aptly put it, "in old age our health is sometimes much more influenced by the diet of our mother during pregnancy than food at the current moment of life."

Inherited fate

The most studied mechanism of epigenetic regulation of gene activity is the methylation process, which consists in the addition of a methyl group (one carbon atom and three hydrogen atoms) to the cytosine bases of DNA. Methylation can affect gene activity in several ways. In particular, methyl groups can physically interfere with the contact of a transcription factor (a protein that controls the synthesis of messenger RNA on a DNA template) with specific regions of DNA. On the other hand, they work in conjunction with methylcytosine-binding proteins, participating in the process of chromatin remodeling, the substance that makes up chromosomes, the repository of hereditary information.

DNA methylation
Methyl groups attach to cytosine bases without destroying or changing DNA, but affecting the activity of the corresponding genes. There is also a reverse process - demethylation, in which methyl groups are removed and the initial activity of genes is restored "border \u003d" 0 "\u003e

Methylation is involved in many processes associated with the development and formation of all organs and systems in humans. One of them is the inactivation of the X chromosomes in the embryo. As you know, female mammals have two copies of sex chromosomes, designated as the X chromosome, and males are content with one X and one Y chromosome, which is much smaller in size and in the amount of genetic information. To equalize males and females in the amount of gene products (RNA and proteins) produced, most genes on one of the X chromosomes in females are turned off.

The culmination of this process occurs at the blastocyst stage, when the embryo consists of 50-100 cells. In each cell, the chromosome for inactivation (paternal or maternal) is randomly selected and remains inactive in all subsequent generations of this cell. Associated with this process of "mixing" of paternal and maternal chromosomes is the fact that women are much less likely to suffer from diseases associated with the X chromosome.

Methylation plays an important role in cell differentiation, the process by which “universal” embryonic cells develop into specialized tissue and organ cells. Muscle fibers bone, nerve cells - they all appear due to the activity of a strictly defined part of the genome. It is also known that methylation plays a leading role in the suppression of most varieties of oncogenes, as well as some viruses.

DNA methylation has the greatest applied importance of all epigenetic mechanisms, since it is directly related to diet, emotional status, brain activity, and other external factors.

Data well supporting this conclusion were obtained at the beginning of this century by American and European researchers. Scientists examined elderly Dutch people born immediately after the war. Their mothers' pregnancy coincided with a very difficult time, when there was a real famine in Holland in the winter of 1944-1945. Scientists were able to establish: severe emotional stress and a half-starved diet of mothers had the most negative impact on the health of future children. Low birth weight, they were several times more likely to suffer from heart disease, obesity and diabetes in adulthood than their compatriots born a year or two later (or earlier).

Analysis of their genome showed the absence of DNA methylation in those areas where it ensures the preservation of good health. For example, in elderly Dutch people whose mothers survived hunger, methylation of the gene for insulin-like growth factor (IGF) was markedly reduced, due to which the amount of IGF in the blood increased. And this factor, as scientists well know, has an inverse relationship with life expectancy: the higher the level of IGF in the body, the shorter the life.

Later, the American scientist Lambert Lume discovered that in the next generation, children born to the families of these Dutchmen were also born with an abnormally low weight and more often than others suffered from all age-related diseases, although their parents lived quite well and ate well. The genes remembered information about the hungry period of pregnancy of grandmothers and passed it on even through a generation to grandchildren.

The many faces of epigenetics

Epigenetic processes are realized at several levels. Methylation acts at the level of individual nucleotides. The next level is the modification of histones, proteins involved in the packaging of DNA strands. The processes of DNA transcription and replication also depend on this packaging. A separate scientific branch - RNA epigenetics - studies epigenetic processes associated with RNA, including methylation of messenger RNA.

Genes are not a sentence

In addition to stress and malnutrition, the health of the fetus can be affected by numerous substances that distort the normal processes of hormonal regulation. They are called "endocrine disruptors" (destroyers). These substances, as a rule, are of an artificial nature: mankind receives them industrially for their needs.

The most striking and negative example is, perhaps, bisphenol-A, which has been used for many years as a hardener in the manufacture of plastic products. It is found in some types of plastic containers - bottles for water and drinks, food containers.

The negative effect of bisphenol-A on the body is the ability to "destroy" free methyl groups required for methylation, and suppress the enzymes that attach these groups to DNA. Biologists at Harvard Medical School have discovered the ability of bisphenol-A to inhibit the maturation of the egg and thereby lead to infertility. Their colleagues at Columbia University have discovered the ability of bisphenol-A to blur differences between the sexes and stimulate the birth of offspring with homosexual tendencies. Under the influence of bisphenol, the normal methylation of genes encoding receptors for estrogens and female sex hormones was disrupted. Because of this, male mice were born with a "feminine" character, docile and calm.

Fortunately, there are foods that have a positive effect on the epigenome. For example, regular consumption of green tea can reduce the risk of cancer, because it contains a certain substance (epigallocatechin-3-gallate) that can activate tumor suppressor genes (suppressors) by demethylating their DNA. In recent years, genistein, a modulator of epigenetic processes, contained in soy products, has been popular. Many researchers associate the content of soy in the diet of the inhabitants of Asian countries with their lower susceptibility to certain age-related diseases.

The study of epigenetic mechanisms helped to understand an important truth: a lot in life depends on ourselves. In contrast to relatively stable genetic information, epigenetic "tags" under certain conditions can be reversible. This fact allows counting on fundamentally new methods of combating common diseases based on the elimination of those epigenetic modifications that arose in humans under the influence of unfavorable factors. The application of approaches aimed at correcting the epigenome opens up great prospects for us.

Epigenetics is a relatively new branch of genetics, which is called one of the most important biological discoveries since the discovery of DNA. It used to be thought that the set of genes we are born with irreversibly determines our life. However, it is now known that genes can be “turned on” and “turned off”, as well as achieved more or less expression under the influence of various lifestyle factors.

the site will tell you what epigenetics is, how it works, and what you can do to improve your chances of winning the health lottery.

Epigenetics: lifestyle changes are the key to changing genes

Epigenetics - a science that studies the processes leading to a change in gene activity without changing the DNA sequence. Simply put, epigenetics studies the effect of external factors on gene activity.

The Human Genome Project identified 25,000 genes in human DNA. DNA can be called the code that an organism uses to build and rearrange itself. However, genes themselves need "instructions" by which they determine the necessary actions and the timing of their implementation.

Epigenetic modifications are the very instructions.

There are several types of such modifications, but the two main ones are those that affect methyl groups (carbon and hydrogen) and histones (proteins).

To understand how modifications work, imagine that a gene is a light bulb. Methyl groups act as a light switch (i.e. a gene), and histones act as a dimmer (i.e., they regulate the level of gene activity). So, it is believed that a person has four million of these switches, which are activated under the influence of lifestyle and external factors.

Observation of the life of identical twins became the key to understanding the influence of external factors on gene activity. Observations have shown how strong the changes can be in the genes of these twins, who lead different lifestyles in different external conditions.

Ideally, identical twins should have common diseases, but this is often not the case: alcoholism, Alzheimer's disease, bipolar disorder, schizophrenia, diabetes, cancer, Crohn's disease and rheumatoid arthritis can occur in only one twin, depending on various factors. The reason for this is epigenetic drift - age-related changes in gene expression.

Secrets of epigenetics: how lifestyle factors influence genes

Epigenetic research has shown that only 5% of disease-related gene mutations are completely deterministic; the remaining 95% can be influenced by diet, behavior and other environmental factors. The healthy lifestyle program allows you to change the activity of 4,000 to 5,000 different genes.

We are not just the sum of the genes we were born with. It is the person who is the user, it is he who controls his genes. At the same time, it is not so important what kind of "genetic cards" nature handed out to you - it is important what you will do with them.

Epigenetics is in its infancy, and much remains to be learned, but there is evidence of what major lifestyle factors influence gene expression.

1. Eating, sleeping and exercising

Not surprisingly, nutrition can affect the state of your DNA. A diet high in processed carbohydrates leads to DNA "attacks" with high blood glucose levels. On the other hand, DNA damage can be reversed:

• sulforaphane (found in broccoli);
• curcumin (in turmeric);
• epigallocatechin-3-gallate (found in green tea);
• resveratrol (found in grapes and wine).

When it comes to sleep, just a week of sleep deprivation negatively affects the activity of more than 700 genes. The expression of genes (117) is positively affected by sports.

1. Stress, relationships, and even thoughts

Epigeneticists argue that it's not just "material" factors like diet, sleep, and exercise that affect genes. As it turns out, stress, relationships with people and your thoughts are also significant factors affecting gene expression. So:

• meditation suppresses the expression of pro-inflammatory genes, helping to fight inflammation, i.e. protect against Alzheimer's disease, cancer, heart disease and diabetes; at the same time, the effect of this practice is visible after 8 hours of training
• 400 scientific studies have shown that showing gratitude, kindness, optimism, and various techniques that involve the mind and body positively influence gene expression;
• lack of activity, poor diet, persistent negative emotions, toxins and bad habits, as well as trauma and stress, trigger negative epigenetic changes.

Duration of the results of epigenetic changes and the future of epigenetics

One of the most startling and controversial discoveries is that epigenetic changes are passed on to the next generation without changing the gene sequence. Dr. Mitchell Gaynor, author of The Gene Therapy Plan: Take Control of Genetic Fate through Diet and Lifestyle, believes that gene expression is also inherited.

Epigenetics, says Dr. Randy Girtle, proves that we are also responsible for the integrity of our genome. We used to think that everything depends on genes. Epigenetics allows us to understand that our behavior and habits can influence gene expression in future generations.

Epigenetics is a complex science with enormous potential. There is still a lot of work to be done to determine which environmental factors influence our genes and how we can (and can) reverse diseases or prevent them as effectively as possible.

The organism with the environment during the formation of the phenotype. She studies the mechanisms by which, on the basis of genetic information contained in one cell (zygote), due to the different expression of genes in different types of cells, the development of a multicellular organism consisting of differentiated cells can be carried out. It should be noted that many researchers are still skeptical about epigenetics, since within its framework the probability of nongenomic inheritance is allowed as an adaptive response to changes in the external environment, which contradicts the currently dominant genocentric paradigm.

Examples of

One example of epigenetic changes in eukaryotes is the process of cell differentiation. During morphogenesis, totipotent stem cells form various pluripotent embryonic cell lines, which in turn give rise to fully differentiated cells. In other words, one fertilized egg - a zygote - differentiates into different types of cells, including: neurons, muscle cells, epithelium, vascular endothelium, etc., through multiple divisions. This is achieved by activating some genes, and, at the same time, inhibiting others, using epigenetic mechanisms.

A second example can be demonstrated in field mice. In autumn, before the cold snap, they are born with a longer and thicker coat than in spring, although the intrauterine development of "spring" and "autumn" mice occurs against a background of almost identical conditions (temperature, day length, humidity, etc.). Studies have shown that a signal that triggers epigenetic changes leading to an increase in coat length is a change in the gradient of the concentration of melatonin in the blood (it decreases in spring and increases in autumn). Thus, epigenetic adaptive changes (an increase in coat length) are induced even before the onset of cold weather, adaptation to which is beneficial for the body.

Etymology and definitions

The term "epigenetics" (like "epigenetic landscape") was coined by Konrad Waddington in 1942 as a derivative of the words genetics and epigenesis. When Waddington coined the term, the physical nature of genes was not fully understood, so he used it as a conceptual model of how genes might interact with their environment to form a phenotype.

Robin Halliday defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of organisms." Thus, the term "epigenetics" can be used to describe any internal factors that influence the development of an organism, with the exception of the DNA sequence itself.

The modern use of this word in scientific discourse is narrower. The Greek prefix epi- in the word implies factors that influence "over" or "in addition to" genetic factors, which means that epigenetic factors affect in addition to or in addition to traditional molecular factors of heredity.

The similarity with the word "genetics" has given rise to many analogies in the use of the term. "Epigenome" is analogous to the term "genome" and defines the general epigenetic state of the cell. The metaphor "genetic code" has also been adapted, and the term "epigenetic code" is used to describe the set of epigenetic features that create diverse phenotypes in different cells. The term "epimutation" is widely used, which denotes a change in the normal epigenome caused by sporadic factors, which is transmitted in a number of cell generations.

Molecular basis of epigenetics

The molecular basis of epigenetics is quite complex, despite the fact that it does not affect the structure of DNA, but changes the activity of certain genes. This explains why differentiated cells of a multicellular organism express only genes necessary for their specific activity. A feature of epigenetic changes is that they are preserved during cell division. It is known that most epigenetic changes are manifested only within the life of one organism. At the same time, if a change in DNA occurs in a sperm or egg, then some epigenetic manifestations can be transmitted from one generation to the next. In this regard, the question arises, can epigenetic changes in the body really change the basic structure of its DNA? (see Evolution).

Within the framework of epigenetics, such processes are widely studied as: paramutation, genetic bookmarking, genomic imprinting, X-chromosome inactivation, position effect, maternal effects, as well as other mechanisms of gene expression regulation.

Epigenetic studies use a wide range of molecular biology methods, including chromatin immunoprecipitation (various ChIP-on-chip and ChIP-Seq modifications), in situ hybridization, restriction enzyme methylation, identification of DNA adenine methyltransferase (DamID) and bisulfite sequencing. In addition, the use of bioinformatics methods (computer epigenetics) is playing an increasing role.

Mechanisms

DNA methylation and chromatin remodeling

Epigenetic factors affect the expression activity of certain genes at several levels, which leads to a change in the phenotype of a cell or organism. One of the mechanisms of this effect is chromatin remodeling. Chromatin is a complex of DNA with histone proteins: DNA is wrapped around histone proteins, which are represented by spherical structures (nucleosomes), as a result of which its compaction in the nucleus is ensured. The intensity of gene expression depends on the density of histones in actively expressed regions of the genome. Chromatin remodeling is a process of actively changing the "density" of nucleosomes and the affinity of histones with DNA. It is achieved in two ways described below.

DNA methylation

The most well-studied epigenetic mechanism to date is the methylation of DNA cytosine bases. The beginning of intensive studies of the role of methylation in the regulation of genetic expression, including aging, was laid back in the 70s of the last century by the pioneering works of BF Vanyushin and GD Berdyshev et al. The process of DNA methylation consists in the attachment of a methyl group to the cytosine of the CpG dinucleotide at the C5 position of the cytosine ring. DNA methylation is mainly inherent in eukaryotes. In humans, about 1% of genomic DNA is methylated. Three enzymes called DNA methyltransferases 1, 3a, and 3b (DNMT1, DNMT3a and DNMT3b) are responsible for the DNA methylation process. It is assumed that DNMT3a and DNMT3b are de novo methyltransferases, which carry out the formation of the DNA methylation pattern at early stages of development, while DNMT1 carries out DNA methylation at later stages of an organism's life. The methylation function is to activate / deactivate a gene. In most cases, methylation leads to suppression of gene activity, especially during methylation of its promoter regions, and demethylation leads to its activation. It has been shown that even insignificant changes in the degree of DNA methylation can significantly change the level of genetic expression.

Histone modifications

Although amino acid modifications in histones occur throughout the protein molecule, N-tail modifications occur much more frequently. These modifications include: phosphorylation, ubiquitylation, acetylation, methylation, sumoylation. Acetylation is the most studied histone modification. Thus, acetylation of histone H3 tail lysines by acetyltransferase K14 and K9 correlates with transcriptional activity in this region of the chromosome. This is due to the fact that the acetylation of lysine changes its positive charge to neutral, which makes it impossible for it to bond with negatively charged phosphate groups in DNA. As a result, histones are detached from the DNA, which leads to the landing on the "naked" DNA of the SWI / SNF complex and other transcription factors that trigger transcription. This is the cis model of epigenetic regulation.

Histones are able to maintain their modified state and act as a template for the modification of new histones that bind to DNA after replication.

The mechanism of reproduction of epigenetic tags is more studied for DNA methylation than for histone modifications. Thus, the DNMT1 enzyme has a high affinity for 5-methylcytosine. When DNMT1 finds a "hemimethylated site" (a site where cytosine is methylated in only one DNA strand), it methylates cytosine on a second strand at the same site.

Prions

MicroRNA

Recently, much attention has been drawn to the study of the role of small interfering RNAs (si-RNA) in the regulation of genetic activity. Interfering RNAs can alter the stability and translation of mRNAs by modeling polysome functions and chromatin structure.

Value

Epigenetic inheritance in somatic cells plays an essential role in the development of a multicellular organism. The genome of all cells is almost the same, at the same time, a multicellular organism contains differently differentiated cells that perceive environmental signals in different ways and perform various functions... It is epigenetic factors that provide "cellular memory".

Medicine

Both genetic and epigenetic phenomena have a significant impact on human health. Several diseases are known that arise from a violation of gene methylation, as well as from hemizygosity for a gene subject to genomic imprinting. For many organisms, the relationship between the acetylation / deacetylation activity of histones and lifespan has been proven. Perhaps these same processes affect the life expectancy of people.

Evolution

Although epigenetics is mainly viewed in the context of cellular memory, there are also a number of transgenerative epigenetic effects in which genetic changes are passed on to offspring. Unlike mutations, epigenetic changes are reversible and possibly targeted (adaptive). Since most of them disappear after several generations, they can only be temporary adaptations. The question of the possibility of the influence of epigenetics on the frequency of mutations in a particular gene is also being actively discussed. It has been shown that the APOBEC / AID family of cytosine deaminases is involved in both genetic and epigenetic inheritance using similar molecular mechanisms. More than 100 cases of transgenerative epigenetic phenomena have been found in many organisms.

Epigenetic effects in humans

Genomic imprinting and related diseases

Some human diseases are associated with genomic imprinting, the phenomenon in which the same genes have a different methylation pattern depending on which parent they are from. The most famous cases of imprinting-related diseases are Angelman syndrome and Prader-Willi syndrome. Both are caused by a partial deletion in the 15q region. This is due to the presence of genomic imprinting at this locus.

Transgenerative epigenetic effects

Marcus Pembrey et al found that grandchildren (but not granddaughters) of men who were exposed to hunger in Sweden in the 19th century are less prone to cardiovascular disease, but more susceptible to diabetes, which, according to the author, is an example epigenetic heredity.

Cancer and developmental disorders

Many substances have the properties of epigenetic carcinogens: they lead to an increase in the incidence of tumors without showing a mutagenic effect (for example: diethylstilbestrol arsenite, hexachlorobenzene, and nickel compounds). Many teratogens, in particular diethylstilbestrol, have a specific effect on the fetus at the epigenetic level.

Changes in histone acetylation and DNA methylation lead to the development of prostate cancer by altering the activity of various genes. Diet and lifestyle can affect gene activity in prostate cancer.

In 2008, the US National Institutes of Health announced that $ 190 million would be spent on epigenetics research over the next 5 years. According to some researchers who pioneered the allocation of funds, epigenetics may play a greater role in the treatment of human diseases than genetics.

Epigenome and aging

In recent years, a large body of evidence has accumulated that epigenetic processes play an important role in the later stages of life. In particular, with aging, large-scale changes in methylation patterns occur. It is assumed that these processes are under genetic control. Usually, the largest amount of methylated cytosine bases is observed in DNA isolated from embryos or newborn animals, and this amount gradually decreases with age. A similar decrease in DNA methylation levels has been found in cultured lymphocytes from mice, hamsters and humans. It is systematic in nature, but it can be tissue- and gene-specific. For example, Tra et al. (Tra et al., 2002), when comparing more than 2000 loci in T-lymphocytes isolated from the peripheral blood of newborns, as well as middle-aged and older people, they found that 23 of these loci undergo hypermethylation with age and 6 - hypomethylation, and similar changes in the methylation pattern were also found in other tissues: pancreas, lungs, and esophagus. Pronounced epigenetic distortions were found in patients with Hutchinson-Guildford progyria.

It is assumed that demethylation with age leads to chromosomal rearrangements due to the activation of mobile genetic elements (MGE), which are usually suppressed by DNA methylation (Barbot et al., 2002; Bennett-Baker, 2003). A systematic age-related decrease in methylation levels may, at least in part, be the cause of many complex diseases that cannot be explained using classical genetic views. Another process that occurs in ontogenesis in parallel with demethylation and affects the processes of epigenetic regulation is chromatin condensation (heterochromatinization), which leads to a decrease in genetic activity with age. In a number of studies, age-dependent epigenetic changes were also demonstrated in germ cells; the direction of these changes seems to be gene-specific.

Literature

• Nessa Carey... Epigenetics: How modern biology is rewriting our understanding of genetics, disease and heredity. - Rostov-on-Don: Phoenix, 2012 .-- ISBN 978-5-222-18837-8.

Notes

1. New research links common RNA modification to obesity
2. http://woman.health-ua.com/article/475.html Epigenetic Epidemiology of Age-Associated Diseases
4. Holliday, R., 1990. Mechanisms for the control of gene activity during development. Biol. Rev. Cambr. Philos. Soc. 65, 431-471
5. Epigenetics. Bio-Medicine.org. Retrieved 2011-05-21.
6. V.L. Chandler (2007). Paramutation: From Maize to Mice. Cell 128 (4): 641-645. doi: 10.1016 / j.cell.2007.02.007. PMID 17320501.
7. Jan Sapp, Beyond the Gene. 1987 Oxford University Press. Jan Sapp, "Concepts of organization: the leverage of ciliate protozoa." In S. Gilbert ed., Developmental Biology: A Comprehensive Synthesis, (New York: Plenum Press, 1991), 229-258. Jan Sapp, Genesis: The Evolution of Biology Oxford University Press, 2003.
8. Oyama, Susan; Paul E. Griffiths, Russell D. Gray (2001). MIT Press. ISBN 0-26-265063-0.
9. Verdel et al, 2004
10. Matzke, Birchler, 2005
11. O.J. Rando and K.J. Verstrepen (2007). Timescales of Genetic and Epigenetic Inheritance. Cell 128 (4): 655-668. doi: 10.1016 / j.cell.2007.01.023. PMID 17320504.
12. Jablonka, Eva; Gal Raz (June 2009). Transgenerational Epigenetic Inheritance: Prevalence, Mechanisms, and Implications for the Study of Heredity and Evolution. The Quarterly Review of Biology 84 (2): 131-176. doi: 10.1086 / 598822. PMID 19606595.
13. J.H.M. Knoll, R.D. Nicholls, R.E. Magenis, J.M. Graham Jr, M. Lalande, S.A. Latt (1989). "Angelman and Prader-Willi syndromes share a common chromosome deletion but differ in parental origin of the deletion." American Journal of Medical Genetics 32 (2): 285-290. doi: 10.1002 / ajmg.1320320235. PMID 2564739.
14. Pembrey ME, Bygren LO, Kaati G, et al .. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006; 14: 159-66. PMID 16391557. Robert Winston refers to this study in a lecture; see also discussion at Leeds University, here

Epigenetics is a relatively recent branch of biological science and is not yet as widely known as genetics. It is understood as a branch of genetics that studies the inherited changes in gene activity during the development of an organism or cell division.

Epigenetic changes are not accompanied by a rearrangement of the nucleotide sequence in deoxyribonucleic acid (DNA).

In the body, there are various regulatory elements in the genome itself that control the work of genes, including depending on internal and external factors. For a long time, epigenetics was not recognized, since there was little information about the nature of epigenetic signals and the mechanisms of their implementation.

Human genome structure

In 2002, as a result of many years of efforts by a large number of scientists different countries the decoding of the structure of the human hereditary apparatus, which is contained in the main DNA molecule, has been completed. This is one of the outstanding achievements of biology at the beginning of the 21st century.

DNA, which contains all the hereditary information about a given organism, is called the genome. Genes are individual regions that occupy a very small part of the genome, but at the same time form its basis. Each gene is responsible for transmitting data on the structure of ribonucleic acid (RNA) and protein in the human body. The structures that convey hereditary information are called coding sequences. As a result of the Genome project, data were obtained according to which the human genome was estimated at more than 30,000 genes. Currently, due to the emergence of new results of mass spectrometry, the genome is estimated to contain about 19,000 genes.

The genetic information of each person is contained in the cell nucleus and is located in special structures called chromosomes. Each somatic cell contains two complete sets of (diploid) chromosomes. Each single set (haploid) contains 23 chromosomes - 22 ordinary (autosomes) and one sex chromosome - X or Y.

The DNA molecules contained in all chromosomes of every human cell are two polymer chains twisted into a regular double helix.

Both chains hold each other with four bases: adenine (A), cytosine (C), guanine (G), and thiamine (T). Moreover, the base A on one chain can connect only with the base T on the other chain, and similarly the base G can connect with the base C. This is called the principle of base pairing. In other cases, mating violates the entire integrity of the DNA.

DNA exists as a tight complex with specialized proteins, and together they make up chromatin.

Histones are nucleoproteins, the main constituent of chromatin. They tend to form new substances by attaching two structural elements to a complex (dimer), which is a feature for subsequent epigenetic modification and regulation.

The DNA that stores genetic information is self-replicating (doubling) with each cell division, i.e., it removes exact copies from itself (replication). During cell division, the bonds between the two strands of the DNA double helix break down and the strands of the helix separate. Then a daughter DNA strand is built on each of them. As a result, the DNA molecule doubles, daughter cells are formed.

DNA serves as a matrix on which different RNAs are synthesized (transcription). This process (replication and transcription) takes place in the nucleus of cells, and it begins with a region of a gene called a promoter, on which protein complexes that copy DNA are bound to form messenger RNA (mRNA).

In turn, the latter serves not only as a carrier of DNA information, but also as a carrier of this information for the synthesis of protein molecules on ribosomes (translation process).

It is now known that the human gene zones encoding proteins (exons) occupy only 1.5% of the genome. Most of the genome is not related to genes and is inert in terms of information transfer. Identified areas of a gene that do not encode proteins are called introns.

The first copy of mRNA, obtained from DNA, contains the entire set of exons and introns. Thereafter, specialized protein complexes remove all intron sequences and link exons to each other. This editing process is called splicing.

Epigenetics explains one of the mechanisms by which a cell is able to control the synthesis of the protein it produces, first of all determining how many copies of mRNA can be obtained from DNA.

So, the genome is not a frozen part of DNA, but a dynamic structure, a repository of information that cannot be reduced to genes alone.

The development and functioning of individual cells and the organism as a whole are not automatically programmed in one genome, but depend on many different internal and external factors. With the accumulation of knowledge, it turns out that in the genome itself there are multiple regulatory elements that control the work of genes. Now this is confirmed in many experimental studies on animals.

When dividing during mitosis, daughter cells can inherit from their parents not only direct genetic information in the form of a new copy of all genes, but also a certain level of their activity. This type of inheritance of genetic information is called epigenetic inheritance.

Epigenetic mechanisms of gene regulation

The subject of epigenetics is the study of the inheritance of gene activity, which is not associated with a change in the primary structure of the DNA included in their composition. Epigenetic changes are aimed at the adaptation of the organism to the changing conditions of its existence.

The term "epigenetics" was first proposed by the English geneticist Waddington in 1942. The difference between genetic and epigenetic mechanisms of inheritance lies in the stability and reproducibility of effects.

An unlimited number of genetic traits are fixed until a mutation occurs in the gene. Epigenetic modifications are usually displayed in cells within the lifetime of one generation of an organism. When these changes are passed on to the next generations, they can be reproduced in 3-4 generations, and then, if the stimulating factor disappears, these transformations disappear.

The molecular basis of epigenetics is characterized by the modification of the genetic apparatus, i.e., the activation and repression of genes that do not affect the primary sequence of DNA nucleotides.

Epigenetic regulation of genes is carried out at the level of transcription (time and nature of gene transcription), during the selection of mature mRNAs for their transport into the cytoplasm, during the selection of mRNAs in the cytoplasm for translation on ribosomes, destabilization of certain types of mRNA in the cytoplasm, selective activation, inactivation of protein molecules after them synthesis.

The collection of epigenetic markers represents the epigenome. Epigenetic transformations can affect the phenotype.

Epigenetics plays an important role in the functioning of healthy cells, ensuring the activation and repression of genes, in the control of transposons, i.e., DNA regions that can move within the genome, as well as in the exchange of genetic material in chromosomes.

Epigenetic mechanisms are involved in genomic imprinting (fingerprint), a process in which the expression of certain genes is carried out depending on which parent the alleles came from. Imprinting is realized through the process of DNA methylation in promoters, as a result of which gene transcription is blocked.

Epigenetic mechanisms provide the initiation of processes in chromatin through histone modifications and DNA methylation. Over the past two decades, ideas about the mechanisms of regulation of eukaryotic transcription have changed significantly. The classical model assumed that the level of expression is determined by transcription factors that bind to regulatory regions of the gene that initiate the synthesis of messenger RNA. Histones and non-histone proteins were assigned the role of a passive packaging structure to ensure compact packing of DNA in the nucleus.

In subsequent studies, the role of histones in the regulation of translation was shown. The so-called histone code was discovered, that is, the modification of histones, which is not the same in different regions of the genome. Modified histone codes can lead to the activation and repression of genes.

Various parts of the genome structure undergo modifications. Methyl, acetyl, phosphate groups and larger protein molecules can be attached to the terminal residues.

All modifications are reversible and for each there are enzymes that install or remove it.

DNA methylation

In mammals, DNA methylation (epigenetic mechanism) was studied earlier than others. It has been shown to correlate with gene repression. Experimental data show that DNA methylation is a defense mechanism that suppresses a significant part of the genome of a foreign nature (viruses, etc.).

DNA methylation in the cell controls all genetic processes: replication, repair, recombination, transcription, X-chromosome inactivation. Methyl groups disrupt DNA-protein interactions, preventing the binding of transcription factors. DNA methylation affects the structure of chromatin, blocks transcriptional repressors.

Indeed, an increase in the level of DNA methylation correlates with a relative increase in the content of noncoding and repetitive DNA in the genomes of higher eukaryotes. Experimental evidence suggests that this is because DNA methylation serves primarily as a defense mechanism to suppress a significant portion of the foreign genome (replicated roaming elements, viral sequences, other repetitive sequences).

The methylation profile - activation or inhibition - varies depending on environmental factors. The effect of DNA methylation on chromatin structure is of great importance for the development and functioning of a healthy organism in order to suppress a significant part of the genome of foreign origin, i.e., replicated moving elements, viral and other repetitive sequences.

DNA methylation occurs through a reversible chemical reaction of a nitrogenous base - cytosine, as a result of which the methyl group CH3 is attached to carbon to form methylcytosine. This process is catalyzed by the enzymes DNA methyltransferases. For methylation of cytosine, guanine is required, resulting in the formation of two nucleotides separated by phosphate (CpG).

The accumulation of inactive CpG sequences is called CpG islands. The latter are represented unevenly in the genome. Most of them are found in gene promoters. DNA methylation occurs in gene promoters, in transcribed regions, and also in intergenic spaces.

Hypermethylated islets cause gene inactivation, which disrupts the interaction of regulatory proteins with promoters.

DNA methylation has a profound effect on gene expression and, ultimately, on the function of cells, tissues and the body as a whole. A direct relationship was established between the high level of DNA methylation and the number of repressed genes.

Removal of methyl groups from DNA as a result of the absence of methylase activity (passive demethylation) occurs after DNA replication. Active demethylation involves an enzymatic system that converts 5-methylcytosine into cytosine regardless of replication. The methylation profile changes depending on the environmental factors in which the cell is located.

Loss of the ability to maintain DNA methylation can lead to immunodeficiency, malignant tumors, and other diseases.

For a long time, the mechanism and enzymes involved in the process of active demethylation of DNA remained unknown.

Acetylation of histones

There are a large number of post-translational histone modifications that form chromatin. In the 1960s, Vincent Alfrey identified acetylation and phosphorylation of histones from many eukaryotes.

The enzymes for acetylation and deacetylation (acetyltransferase) of histones play a role in the course of transcription. These enzymes catalyze the acetylation of local histones. Deacetylases of histones repress transcription.

The acetylation effect is the weakening of the bond between DNA and histones due to a change in charge, as a result of which chromatin becomes available to transcription factors.

Acetylation is the attachment of a chemical acetyl group (the amino acid lysine) to a free portion of histone. Like DNA methylation, lysine acetylation is an epigenetic mechanism for altering the expression of genes that do not affect the original gene sequence. The template by which the modifications of nuclear proteins take place has come to be called the histone code.

Histone modifications are fundamentally different from DNA methylation. DNA methylation is a very stable epigenetic intervention that is more likely to be fixed in most cases.

The vast majority of histone modifications are more variable. They affect the regulation of gene expression, maintenance of chromatin structure, cell differentiation, carcinogenesis, development genetic diseases, aging, DNA repair, replication, translation. If histone modifications are beneficial to the cell, then they can last for quite a long time.

One of the mechanisms of interaction between the cytoplasm and the nucleus is phosphorylation and / or dephosphorylation of transcription factors. Histones were among the first proteins to be discovered to be phosphorylated. This is done using protein kinases.

Phosphorylated transcription factors control genes, including genes that regulate cell proliferation. With such modifications, structural changes occur in the molecules of chromosomal proteins that lead to functional changes in chromatin.

In addition to the post-translational modifications of histones described above, there are larger proteins, such as ubiquitin, SUMO, and others, which can be attached via a covalent bond to the side amino groups of the target protein, affecting their activity.

Epigenetic changes can be inherited (transgenerative epigenetic inheritance). However, unlike genetic information, epigenetic changes can be reproduced in 3-4 generations, and in the absence of a factor that stimulates these changes, they disappear. The transfer of epigenetic information occurs in the process of meiosis (division of the cell nucleus with a halving of the number of chromosomes) or mitosis (cell division).

Histone modifications play a fundamental role in normal processes and disease.

Regulatory RNAs

RNA molecules perform many functions in the cell. One of them is the regulation of gene expression. Regulatory RNAs are responsible for this function, which include antisense RNA (aRNA), microRNA (miRNA) and small interfering RNAs (siRNA)

The mechanism of action of different regulatory RNAs is similar and consists in suppressing gene expression, which is realized by complementary attachment of regulatory RNA to mRNA, with the formation of a double-stranded molecule (dsRNA). By itself, the formation of dsRNA leads to disruption of the binding of mRNA to the ribosome or other regulatory factors, suppressing translation. Also, after the formation of a duplex, the manifestation of the phenomenon of RNA interference is possible - the Dicer enzyme, having found double-stranded RNA in the cell, “cuts” it into fragments. One of the chains of such a fragment (siRNA) is bound by the RISC protein complex (RNA-induced silencing complex).

As a result of RISC activity, a single-stranded RNA fragment binds to the complementary sequence of the mRNA molecule and causes the mRNA to be cleaved by a protein of the Argonaute family. These events lead to suppression of the expression of the corresponding gene.

The physiological functions of regulatory RNAs are diverse - they act as the main non-protein regulators of ontogenesis, complement the "classical" scheme of gene regulation.

Genomic imprinting

A person has two copies of each gene, one of which is inherited from the mother, the other from the father. Both copies of each gene have the ability to be active in any cell. Genomic imprinting is epigenetically selective expression of only one of the allelic genes inherited from parents. Genomic imprinting affects both male and female offspring. Thus, an imprinted gene active on the maternal chromosome will be active on the maternal chromosome and “silent” on the paternal chromosome in all male and female children. Genes subject to genomic imprinting mainly encode factors that regulate embryonic and neonatal growth.

Imprinting is a complex system that can break. Imprinting is observed in many patients with chromosomal deletions (loss of a part of chromosomes). There are known diseases that occur in humans due to impaired functioning of the imprinting mechanism.

Prions

In the last decade, attention has been drawn to prions, proteins that can induce inherited phenotypic changes without changing the DNA nucleotide sequence. In mammals, the prion protein is located on the cell surface. Under certain conditions, the normal shape of prions can change, which modulates the activity of this protein.

Wikner expressed confidence that this class of proteins is one of many that make up a new group of epigenetic mechanisms that require further study. It can be in a normal state, and in an altered state, prion proteins can spread, that is, become infectious.

Initially, prions were discovered as infectious agents of a new type, but now they are considered to be a general biological phenomenon and are carriers of a new type of information stored in the protein conformation. The prion phenomenon underlies epigenetic inheritance and the regulation of gene expression at the post-translational level.

Epigenetics in Practical Medicine

Epigenetic modifications control all stages of development and functional activity of cells. Violation of the mechanisms of epigenetic regulation is directly or indirectly associated with a variety of diseases.

Diseases with epigenetic etiology include imprinting diseases, which, in turn, are divided into gene and chromosomal ones, in total there are currently 24 nosologies.

In diseases of gene imprinting, monoallelic expression is observed at the chromosome loci of one of the parents. The cause is point mutations in genes that are differentially expressed depending on the maternal and paternal origin and lead to specific methylation of cytosine bases in the DNA molecule. These include: Prader-Willi syndrome (deletion in the paternal chromosome 15) - manifested by craniofacial dysmorphism, short stature, obesity, muscle hypotonia, hypogonadism, hypopigmentation and mental retardation; Angelman syndrome (deletion of a critical region located on the 15th maternal chromosome), the main signs of which are microbrachycephaly, an enlarged lower jaw, protruding tongue, macrostomy, rare teeth, hypopigmentation; Beckwitt-Wiedemann syndrome (a violation of methylation in the short arm of the 11th chromosome), manifested by the classic triad, including macrosomia, omphalocele, macroglossia, etc.

Among the most important factors affecting the epigenome are nutrition, physical activity, toxins, viruses, ionizing radiation, etc. A particularly sensitive period to changes in the epigenome is the prenatal period (especially covering two months after conception) and the first three months after birth. During early embryogenesis, the genome removes most of the epigenetic modifications received from previous generations. But the reprogramming process continues throughout life.

Some types of tumors, diabetes mellitus, obesity, bronchial asthma, various degenerative and other diseases can be attributed to diseases where the violation of gene regulation is part of the pathogenesis.

Epigone in cancer is characterized by global changes in DNA methylation, histone modification, as well as a change in the expression profile of chromatin-modifying enzymes.

Tumor processes are characterized by inactivation through hypermethylation of key suppressor genes and through hypomethylation by activation of a number of oncogenes, growth factors (IGF2, TGF) and mobile repeating elements located in heterochromatin regions.

Thus, in 19% of cases of hypernephroid tumors of the kidney, the DNA of the islets of CpG was hypermethylated, and in breast cancer and non-small cell lung carcinoma, a relationship was found between the levels of histone acetylation and the expression of a tumor suppressor - the lower the levels of acetylation, the weaker the gene expression.

Currently, anticancer drugs based on the suppression of the activity of DNA methyltransferases have already been developed and introduced into practice, which leads to a decrease in DNA methylation, activation of tumor suppressor genes and a slowdown in the proliferation of tumor cells. So, for the treatment of myelodysplastic syndrome in complex therapy, the drugs decitabine (Decitabine) and azacytidine (Azacitidine) are used. Since 2015, for the treatment of multiple myeloma in combination with classical chemotherapy, panobinostat (Panibinostat), which is a histone deacylase inhibitor, has been used. According to clinical studies, these drugs have a pronounced positive effect on the survival rate and quality of life of patients.

Changes in the expression of certain genes can also occur as a result of environmental factors acting on the cell. In the development of type 2 diabetes mellitus and obesity, the so-called "economical phenotype hypothesis" plays a role, according to which a lack of nutrients during embryonic development leads to the development of a pathological phenotype. In animal models, a region of DNA (locus Pdx1) was identified, in which, under the influence of malnutrition, the level of histone acetylation decreased, while a slowdown in division and impaired differentiation of B-cells of the islets of Langerhans and the development of a condition similar to type 2 diabetes were observed.

The diagnostic capabilities of epigenetics are also actively developing. New technologies are emerging that can analyze epigenetic changes (DNA methylation level, microRNA expression, post-translational histone modifications, etc.), such as chromatin immunoprecipitation (CHIP), flow cytometry, and laser scanning, which suggests that biomarkers will be identified in the near future. for the study of neurodegenerative diseases, rare, multifactorial diseases and malignant neoplasms and are introduced as methods of laboratory diagnostics.

So, epigenetics is currently developing rapidly. Progress in biology and medicine is associated with it.

Literature

1. Ezkurdia I., Juan D., Rodriguez J. M. et al. Multiple evidence strands suggest that there may be as few as 19,000 human protein-coding genes // Human Molecular Genetics. 2014, 23 (22): 5866-5878.
2. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome // Nature. 2001, Feb. 409 (6822): 860-921.
3. Xuan D., Han Q., Tu Q. et al. Epigenetic Modulation in Periodontitis: Interaction of Adiponectin and JMJD3-IRF4 Axis in Macrophages // Journal of Cellular Physiology. 2016, May; 231 (5): 1090-1096.
4. Waddington C. H. The Epigenotpye // Endeavor. 1942; 18-20.
5. Bochkov N.P.Clinical genetics. M .: Geotar. Med, 2001.
6. Jenuwein T., Allis C. D.Translating the Histone Code // Science. 2001 Aug 10; 293 (5532): 1074-1080.
7. Kovalenko T.F. Methylation of the mammalian genome // Molecular Medicine. 2010. No. 6. S. 21-29.
8. Alice D., Jenyuwein T., Reinberg D. Epigenetics. Moscow: Technosphere, 2010.
9. Taylor P. D., Poston L. Development programming of obesity in mammals // Experemental Physiology. 2006. No. 92. P. 287-298.
10. Lewin B. Genes. M .: BINOM, 2012.
11. Plasschaert R. N., Bartolomei M. S. Genomic imprinting in development, growth, behavior and stem cells // Development. 2014, May; 141 (9): 1805-1813.
12. Wickner R. B., Edskes H. K., Ross E. D.et al. Prion genetics: new rules for a new kind of gene // Annu Rev Genet. 2004; 38: 681-707.
13. Mutovin G. R. Clinical genetics. Genomics and proteomics of hereditary pathology: textbook. allowance. 3rd ed., Rev. and add. 2010.
14. Romantsova T.I.Obesity epidemic: obvious and probable causes // Obesity and metabolism. 2011, No. 1, p. 1-15.
15. Bégin P., Nadeau K. C. Epigenetic regulation of asthma and allergic disease // Allergy Asthma Clin Immunol. 2014, May 28; 10 (1): 27.
16. Martínez J. A., Milagro F. I., Claycombe K. J., Schalinske K. L. Epigenetics in Adipose Tissue, Obesity, Weight Loss, and Diabetes // Advances in Nutrition. 2014, Jan 1; 5 (1): 71-81.
17. Dawson M. A., Kouzarides T. Cancer epigenetics: from mechanism to therapy // Cell. 2012, Jul 6; 150 (1): 12-27.
18. Kaminskas E., Farrell A., Abraham S., Baird A. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes // Clin Cancer Res. 2005, May 15; 11 (10): 3604-3608.
19. Laubach J. P., Moreau P., San-Miguel J..F, Richardson P. G. Panobinostat for the Treatment of Multiple Myeloma // Clin Cancer Res. 2015, Nov 1; 21 (21): 4767-4773.
20. Bramswig N. C., Kaestner K. H. Epigenetics and diabetes treatment: an unrealized promise? // Trends Endocrinol Metab. 2012, Jun; 23 (6): 286-291.
21. Sandovici I., Hammerle C. M., Ozanne S. E., Constância M. Developmental and environmental epigenetic programming of the endocrine pancreas: consequences for type 2 diabetes // Cell Mol Life Sci. 2013, May; 70 (9): 1575-1595.
22. Szekvolgyi L., Imre L., Minh D. X. et al. Flow cytometric and laser scanning microscopic approaches in epigenetics research // Methods Mol Biol. 2009; 567: 99-111.

V. V. Smirnov 1, doctor of Medical Sciences, Professor
G. E. Leonov

FGBOU IN RNIMU them. N.I. Pirogova, Ministry of Health of the Russian Federation, Moscow

Epigenetics is a branch of genetics that has recently emerged as an independent field of research. But today this young dynamic science offers a revolutionary view on the molecular mechanisms of development of living systems.

One of the most daring and inspiring epigenetic hypotheses that the activity of many genes is influenced from the outside, is now being confirmed in many experiments on model animals. Researchers are cautious in their comments on their results, but do not rule out that Homo sapiens does not fully depend on heredity, which means it can purposefully affect it.

In the long term, if scientists are right and they manage to find the keys to the mechanisms of gene control, the person will become subject to the physical processes occurring in the body. Aging may well be among them.

In fig. mechanism of RNA interference.

DsRNA molecules can be an RNA hairpin or two paired RNA strands complementary to each other.
Long dsRNA molecules are cut (processed) in the cell into short ones by the Dicer enzyme: one of its domains specifically binds to the end of the dsRNA molecule (marked with an asterisk), while the other produces breaks (marked with white arrows) in both dsRNA strands.

As a result, a double-stranded RNA 20-25 nucleotides long (siRNA) is formed, and Dicer proceeds to the next cycle of dsRNA cleavage, binding to its newly formed end.

These siRNAs can be incorporated into a complex containing the Argonaute protein (AGO). One of the siRNA strands in a complex with the AGO protein finds in the cell complementary messenger RNA (mRNA) molecules. AGO cuts the target mRNA molecules, causing the mRNA to degrade or stop the translation of the mRNA on the ribosome. Short RNAs can also suppress transcription (RNA synthesis) of a gene homologous to them in the nucleotide sequence in the nucleus.
(drawing, diagram and commentary / magazine "Nature" No. 1, 2007)

Other, not yet known, mechanisms are also possible.
The difference between epigenetic and genetic mechanisms of inheritance is in their stability, reproducibility of effects. Genetically determined traits can be reproduced indefinitely until a certain change (mutation) occurs in the corresponding gene.
Epigenetic changes induced by certain stimuli are usually reproduced in a series of cell generations within the life of one organism. When they are passed on to the next generations, no more than 3-4 generations can be reproduced, and then, if the stimulus that induced them disappears, they gradually fade away.

How does it look at the molecular level? Epigenetic markers, as it is customary to call these chemical complexes, are they not in the nucleotides that form the structural sequence of the DNA molecule, but they directly capture certain signals?

Quite right. Epigenetic markers are really not in nucleotides, but ON them (methylation) or OUT of them (acetylation of chromatin histones, microRNAs).
What happens when these markers are passed on to future generations is best explained using a Christmas tree as an analogy. "Toys" (epigenetic markers) passing from generation to generation are completely removed from it during the formation of a blastocyst (8-cell embryo), and then, during implantation, they are "put on" in the same places where they were before. This has been known for a long time. But what has become known recently, and that completely turned our views in biology, has to do with epigenetic modifications acquired during the life of a given organism.

For example, if an organism is under the influence of a certain influence (heat shock, starvation, etc.), there is a stable induction of epigenetic changes (“buying a new toy”). As suggested earlier, such epigenetic markers are erased without a trace during fertilization and embryo formation and, thus, are not passed on to offspring. It turned out that this is not the case. In a large number of studies in recent years, epigenetic changes induced by environmental stresses in representatives of one generation have been found in representatives of 3-4 subsequent generations. This indicates the possibility of inheriting acquired traits, which until recently was considered absolutely impossible.

What are the most important factors causing epigenetic changes?

These are all factors acting during the sensitive (sensitive) stages of development. In humans, this is the entire period of intrauterine development and the first three months after birth. The most important include nutrition, viral infections, mother's smoking during pregnancy, insufficient production of vitamin D (with sun exposure), maternal stress.
That is, they increase the body's adaptation to changing conditions. And what kind of “messengers” exist between environmental factors and epigenetic processes - no one knows yet.

But, in addition, there is evidence that the most "sensitive" period, during which the main epigenetic modifications are possible, is periconceptual (the first two months after conception). It is possible that attempts of targeted intervention in epigenetic processes even before conception, that is, on germ cells even before the formation of a zygote, may be effective. However, the epigenome remains quite plastic even after the end of the stage of embryonic development; some researchers are trying to correct it in adults as well.

For example, Min Joo Fang ( Ming Zhu Fang) and her colleagues from Rutgers University in New Jersey (USA) found that in adults, using a certain component of green tea (the antioxidant epigallocatechin gallate (EGCG)), it is possible to activate tumor suppressor genes (suppressors) by DNA demethylation.

Now in the United States and Germany, about a dozen drugs are already under development, based on the results of recent studies of epigenetics in the diagnosis of cancer.
What are the key issues in epigenetics now? How can their solution advance the study of the mechanisms (process) of aging?

I believe that the aging process is inherently epigenetic ("as a stage of ontogenesis"). Research in this area began only in recent years, but if they are crowned with success, perhaps humanity will receive a powerful new tool to fight disease and prolong life.
The key issues now are the epigenetic nature of diseases (for example, cancer) and the development of new approaches to their prevention and treatment.
If it is possible to study the molecular epigenetic mechanisms of age-related diseases, it will be possible to successfully counteract their development.

After all, for example, a worker bee lives for 6 weeks, and a queen bee for 6 years.
With complete genetic identity, they differ only in that the future queen bee during development is fed with royal jelly for several days more than an ordinary working bee.

As a result, representatives of these bee castes develop somewhat different epigenotypes. And, despite the external and biochemical similarity, the duration of their life differs 50 times!

In the process of research in the 60s, it was shown that it decreases with age. But have scientists been able to advance in answering the question: why is this happening?

There are a lot of works showing that the characteristics and rate of aging depend on the conditions of early ontogenesis. Most associate this precisely with the correction of epigenetic processes.

DNA methylation does decrease with age; why this happens is not yet known. One of the versions is that this is a consequence of adaptation, an attempt by the body to adapt both to external stresses and to internal "overstress" - aging.

It is possible that the DNA “included” during age-related demethylation is an additional adaptive resource, one of the manifestations of the vitaukt process (as the outstanding gerontologist Vladimir Veniaminovich Frolkis called it) - a physiological process that counteracts aging.

To make changes at the gene level, it is necessary to identify and replace the mutated "letter" of DNA, maybe a portion of genes. So far, the most promising way to carry out such operations is biotechnological. But so far this is an experimental direction and there have not yet been any special breakthroughs in it. Methylation is a more plastic process, it is easier to change it, including with the help of pharmacological drugs. Is it possible to learn to selectively control? What else remains to be done to achieve this?

Methylation is unlikely. It is nonspecific, it affects everything in bulk. You can teach a monkey to beat the keys of the piano, and it will make loud sounds from it, but it is unlikely to perform the Moonlight Sonata. Although there are examples when, with the help of methylation, it was possible to change the phenotype of an organism. The most famous example is with mice - carriers of the mutant agouti gene (I have already cited it). The reversion to the normal coat color occurred in these mice, because the “defective” gene was “turned off” in them due to methylation.

But it is possible to selectively influence gene expression, and interfering RNAs are perfect for this, which act highly specifically, only on "own" ones. Such work is already underway.

For example, recently American researchers transplanted human tumor cells into mice that had suppressed immune system function, which could proliferate and metastasize in immunodeficient mice. Scientists managed to determine those expressed in metastatic cells and, having synthesized the appropriate interfering RNA and injecting it into mice, block the synthesis of "cancer" messenger RNA and, accordingly, suppress tumor growth and metastasis.

That is, based on modern research, we can say that epigenetic signals are the basis of various processes occurring in living organisms. What are they like? What factors influence their formation? Are scientists able to decipher these signals?

Signals can be very different. During development and stress, these are signals, first of all, of a hormonal nature, but there is evidence that even the influence of a low-frequency electromagnetic field of a certain frequency, the intensity of which is a million (!) Times less than the natural electromagnetic field, can lead to the expression of genes of heat shock proteins (HSP70) in cell culture fields. In this case, this field, of course, does not act "energetically", but is a kind of signal "trigger" that "triggers" gene expression. Much is still mysterious here.

For example, recently opened bystander effect("Bystander effect").
In short, its essence is as follows. When we irradiate a culture of cells, they have a wide range of reactions, from chromosomal aberrations to radioadaptive reactions (the ability to withstand large doses of radiation). But if we remove all the irradiated cells and transfer other, non-irradiated ones to the remaining nutrient medium, they will show the same reactions, although no one irradiated them.

It is assumed that the irradiated cells release into the medium some epigenetic “signaling” factors, which cause similar changes in non-irradiated cells. What is the nature of these factors - no one knows yet.

High expectations for improving the quality of life and life expectancy are associated with scientific advances in the field of stem cell research. Will epigenetics live up to its hopes in reprogramming cells? Are there serious prerequisites for this?

If a reliable technique is developed for the "epigenetic reprogramming" of somatic cells into stem cells, this will undoubtedly turn out to be a revolution in biology and medicine. So far, only the first steps have been taken in this direction, but they are encouraging.

A well-known maxim: a person is what he eats. What effect does food have on ours? For example, geneticists at the University of Melbourne, who studied the mechanisms of cellular memory, found that after receiving a single dose of sugar, the cell stores the corresponding chemical marker for several weeks.

There is even a special section of epigenetics - Nutritional Epigenetics, dealing specifically with the issue of the dependence of epigenetic processes on nutritional characteristics. These features are especially important in the early stages of organism development. For example, when a baby is fed not with mother's milk, but with dry nutritional mixtures based on cow's milk, epigenetic changes occur in the cells of his body, which, being fixed by the imprinting (imprinting) mechanism, lead over time to the onset of an autoimmune process in the beta cells of the pancreas and , as a result, type I diabetes.

In fig. the development of diabetes (Fig. increases when pressed with the cursor). In autoimmune diseases such as type 1 diabetes, a person's immune system attacks their own organs and tissues.
Some of the autoantibodies begin to be produced in the body long before the first symptoms of the disease appear. Their identification can help in assessing the risk of developing the disease.
(picture from the magazine "IN THE WORLD OF SCIENCE", July 2007 No. 7)

And inadequate (calorie-limited) nutrition during intrauterine development is a direct path to obesity in adulthood and type II diabetes.

This means that a person is still responsible not only for himself, but also for his descendants: children, grandchildren, great-grandchildren?

Yes, of course, and to a much greater extent than was previously thought.

And what is the epigenetic component in the so-called genomic imprinting?

In genomic imprinting, the same gene is phenotypically manifested differently depending on whether it is passed on to the offspring from the father or mother. That is, if a gene is inherited from the mother, then it is already methylated and not expressed, whereas the gene inherited from the father is not methylated and is expressed.

Genomic imprinting is most actively studied in the development of various hereditary diseases that are transmitted only from ancestors of a certain sex. For example, the juvenile form of Huntington's disease manifests itself only when the mutant allele is inherited from the father, and atrophic myotonia from the mother.
And this despite the fact that the people who cause these diseases are absolutely the same, regardless of whether they are inherited from the father or mother. The differences lie in the "epigenetic prehistory" due to their presence in the maternal or, conversely, paternal, organisms. In other words, they carry the "epigenetic imprint" of the parent's gender. When an ancestor of a certain sex is found in the body, they are methylated (functionally repressed), while the other is demethylated (respectively, expressed), and in the same state are inherited by descendants, leading (or not) to the occurrence of certain diseases.

You have been studying the effects of radiation on the body. Low doses of radiation are known to have a positive effect on the lifespan of fruit flies. fruit fly... Is it possible to train the human body with low doses of radiation? Aleksandr Mikhailovich Kuzin, expressed by him back in the 70s of the last century, the doses that are about an order of magnitude larger than the background ones lead to a stimulating effect.

In Kerala, for example, the background level is not 2, but 7.5 times higher than the "average Indian" level, but neither the incidence of cancer, nor the death rate from it differ from the general Indian population.

(See, for example, the latest on this topic: Nair RR, Rajan B, Akiba S, Jayalekshmi P, Nair MK, Gangadharan P, Koga T, Morishima H, Nakamura S, Sugahara T. Background radiation and cancer incidence in Kerala, India-Karanagappally cohort study. Health Phys. 2009 Jan; 96 (1): 55-66)

In one of the studies, you analyzed data on the dates of birth and death of 105 thousand Kievites who died in the period from 1990 to 2000. What conclusions have been drawn?

The life expectancy of people born at the end of the year (especially in December) turned out to be the longest, and the shortest - among the "April-July" ones. The differences between the minimum and maximum monthly mean values \u200b\u200bwere very large and reached 2.6 years for men and 2.3 years for women. Our results suggest that how long a person will live depends largely on the season of the year they were born.

Is it possible to apply the information obtained?

What would be the recommendations? For example, to conceive children in the spring (preferably in March) so that they are potential centenarians? But this is absurd. Nature does not give everything to some and nothing to others. So it is with "seasonal programming". For example, in studies carried out in many countries (Italy, Portugal, Japan), it was revealed that schoolchildren and students born in late spring - early summer (according to our data - "short-lived") have the highest intellectual abilities. These studies demonstrate the pointlessness of “applied” recommendations for having babies in certain months of the year. But these works, of course, are a serious reason for further scientific research of the mechanisms that determine "programming", as well as the search for means of directed correction of these mechanisms in order to prolong life in the future.

Boris Vanyushin, one of the pioneers of epigenetics in Russia, professor at Moscow State University, wrote in his work "Materialization of Epigenetics or Small Changes with Big Consequences" that the past century was the age of genetics, and the current one is the age of epigenetics.

What makes it possible to assess the position of epiginetics so optimistically?

After the completion of the Human Genome program, the scientific community was shocked: it turned out that information about the structure and functioning of a person is contained in approximately 30 thousand genes (according to various estimates, this is only about 8-10 megabytes of information). Experts who work in the field of epigenetics call it “the second information system” and believe that deciphering the epigenetic mechanisms of control of the development and vital activity of the organism will lead to a revolution in biology and medicine.

For example, a number of studies have already identified typical patterns in such patterns. On their basis, doctors can diagnose the formation of oncological diseases at an early stage.
But is such a project feasible?

Yes, of course, although it is very costly and can hardly be implemented during a crisis. But in the future - quite.

Back in 1970, Vanyushin's group in the magazine "Nature" published data on what regulates cell differentiation, leading to differences in gene expression. And you spoke about it. But if the organism in each cell contains the same genome, then the epigenome of each type of cells has its own, respectively, and the DNA is methylated differently. Considering that there are about two hundred and fifty types of cells in the human body, the amount of information can be colossal.

That is why the project "Human Epigenome" is very difficult (though not hopeless) to implement.

He believes that the most insignificant phenomena can have a huge impact on a person's life: "If a environment plays such a role in changing our genome, then we must build a bridge between biological and social processes. It will absolutely change the way we look at things. "

Is it that serious?

Sure. Now, in connection with the latest discoveries in the field of epigenetics, many scientists are talking about the need for a critical rethinking of many provisions that seemed either unshakable or forever rejected, and even about the need to change the fundamental paradigms in biology. Such a revolution in thinking, of course, can affect in the most significant way all aspects of human life, from worldview and lifestyle to an explosion of discoveries in biology and medicine.

Information about the phenotype is contained not only in the genome, but also in the epigenome, which is plastic and can, changing under the influence of certain environmental stimuli, affect the expression of genes - CONTRADICT TO THE CENTRAL DOGMA OF MOLECULAR BIOLOGY, ACCORDING TO WHICH THE INFORMATION STREAM MAY ONLY COME FROM DNA NOT the other way around.
Epigenetic changes induced in early ontogenesis can be fixed by the imprinting mechanism and change the entire subsequent fate of a person (including psychotype, metabolism, predisposition to diseases, etc.) - ZODIACAL ASTROLOGY.
The reason for evolution, in addition to random changes (mutations) selected by natural selection, is directed, adaptive changes (epimutations) - THE CONCEPT OF CREATIVE EVOLUTION of the French philosopher (Nobel laureate in literature, 1927) Henri BERGSON.
Epimutations can be transmitted from ancestors to descendants - INHERITANCE OF ACQUIRED CHARACTERS, LAMARKISM.

What are the topical questions to be answered in the near future?

How does the development of a multicellular organism occur, what is the nature of the signals that so accurately determine the time of occurrence, structure and function of various organs of the body?

Is it possible, by influencing epigenetic processes, to change organisms in the desired direction?

Is it possible, by adjusting epigenetic processes, to prevent the development of epigenetic diseases, such as diabetes and cancer?

What is the role of epigenetic mechanisms in the aging process, can they help prolong life?

Is it possible that the laws of the evolution of living systems that are incomprehensible in our time (evolution "not according to Darwin") are explained by the involvement of epigenetic processes?

Naturally, this is just my personal list; it may differ for other researchers.