What You did not know about epigenetics: genes and cellular memory
Epigenetics is booming in recent years, the direction of modern science. The most obvious role of epigenetic mechanisms in the processes of development, when the cells of the early embryo, the DNA of which is absolutely identical, there are many different specialized cells of an adult organism.
It turned out, however, that this role is not only limited to development and can manifest itself and after its completion. Recent studies have shown that human health can largely depend on the conditions in which it happened early development. It was also revealed that epigenetic modifications can be transmitted to subsequent generations, affecting various phenotypic manifestations in children and even grandchildren.
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Did you know that our cells have memory? They remember not only what you usually eat for Breakfast, but what to eat during pregnancy, your mother and grandmother. Cells remember, whether you are exercising and how often you consume alcohol.
The memory cell stores your meetings with viruses and how much you are loved as a child. Cellular memory is deciding whether you is prone to obesity and depression. Thanks to cellular memory we are different from chimpanzees, although they are approximately the same part of the genome. This amazing feature of our cells helped to understand the science of epigenetics.
Epigenetics — rather young direction of modern science. And while it is not as widely known as her "sister" — genetics. Translated from the Greek prefix "EPI-" means "over", "above", "over".
If genetics is studying the processes that lead to changes in our genes, DNA, epigenetics investigates changes in the activity of genes in which the primary structure of DNA remains the same. Epigenetics is similar to the "commander" which is in response to external stimuli (such as nutrition, emotional stress, physical stress) gives orders to our genes to enhance or, conversely, to weaken their activity.
Rather, the most succinct and at the same time, the exact definition is the distinguished English biologist, Nobel laureate Peter Medawar: "Genetics proposes, epigenetics disposes."
The development of epigenetics as some areas of molecular biology began in the forties of the last century. Then the British geneticist Conrad Waddington formulated the concept of "epigenetic landscape" (Fig. 1) explaining the formation process of the body.
It took several decades before epigenetics began to be taken seriously as a new scientific discipline. This situation persisted for a long time because epigenetics its findings undermined the established dogma in genetics.
For example, regarding the inheritance of acquired characters. Almost mirror-like repetition of the situation with the discovery of B. McClintock's mobile elements of the genome, in which half-century, few wanted to believe. But after a series of defining works carried out in the 70-ies of the last century, John Gurdon, Robin will name, Halliday, YouTube Vanushina and others epigenetics finally began to take seriously.
And even recently, at the turn of the Millennium, was conducted a series of brilliant experiments, after which it has become clear that epigenetic mechanisms influence gene not only play a critical role in the systems of the body, but can be inherited by multiple generations. In several laboratories was obtained evidence that led geneticists much to think about.
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Figure 1. C. H. Waddington and his picture of the "epigenetic landscape." The ball at the top indicates the original unspecialized cells of the embryo. Under the influence of genetic and epigenetic signals in the cell will set the trajectory of the ontogeny (development), and it will be a specialized cell of heart, liver, etc.
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Figure 2. The eyes of two Drosophila. Different eye color is due to epigenetic changes.
So, in 1998, R. Paro and D. Cavalli carried out experiments with transgenic lines of fruit flies, subjecting them to thermal effects. After that Drosophila changed the colour of the eyes, and this effect — without external influence — remained in several generations (Fig. 2). It had been revealed that the chromosomal element Fab-7 transmit epigenetic inheritance in the process as mitosis and meiosis.
In 2003, American scientists from Duke University Jirtle R. and R. Waterland conducted an experiment with pregnant mice transgenic agouti (yellow agouti (Avy) mouse) that had a yellow coat and a predisposition to obesity (Fig. 3).
They added in feed mice folic acid, vitamin B12, choline and methionine. As a result, appeared normal offspring without deviation. Dietary factors, acting as a donor of methyl groups by DNA methylation neutralized the agouti gene that causes the variation: the phenotype of their Avy-offspring changed due to methylation of the CpG dinucleotide in the Avy locus.
Moreover, the impact of diet continued in several subsequent generations: baby agouti mice are born normal thanks to food additives, and birth of normal mice. Although they have food was ordinary, not rich in methyl groups.
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Figure 3. Experimental mice from the laboratory of Randy Jirtle. It is seen as a change occurs in the coat color of the pups, depending on the reception the mother of the donor of methyl groups, folic acid, vitamin B12, choline and methionine.
Following this, in 2005, the journal Science published the work of Michael Skinner and his colleagues from the University of Washington. They found that if in food of pregnant female rats to add the pesticide vinclozolin, their male offspring sharply reduced the number and viability of sperm.
And these effects persisted for four generations. Was clearly established their relationship with the epigenome: the deterioration of reproductive function were correlated with changes in DNA methylation in the germ line.
Scientists were forced to make a sensational conclusion: stress-induced epigenetic changes not affecting the sequence of nucleotides of DNA that can be secured and transmitted to the next generation!
Fate recorded not only in the genes
Later it turned out that in humans the influence of epigenetic mechanisms (rice. 4, 5) as great. Research, about which more will be discussed, have gained prominence — they are mentioned in almost every research work in epigenetics. Scientists from the Netherlands and the United States at the end of 2000-ies examined elderly Dutch people born immediately after the Second world war.
Pregnancy their mothers went through hard time, when in Holland in the winter of 1944-1945 was real hunger. Scientists managed to establish: severe emotional stress and half-starved diet of the mothers negatively influenced the health of future children.
Born with low weight, they are in adult life more often was subject to heart disease, obesity and diabetes than their countrymen born a year or two later (or earlier).
Analysis of their genome revealed the absence of DNA methylation in those areas where it provides the preservation of good health. So, in older Dutch, whose mothers experienced famine, significantly decreased methylation of the gene insulin-like growth factor 2 (IGF-2), causing the amount of IGF-2 in the blood increased. And this factor is known to have feedback life expectancy: the higher the body's level of IGF, the life is shorter.
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Figure 4. Chromatin structure and mechanisms of epigenetic modifications.Chromatin — complex of proteins and nucleotides, providing secure storage and normal operation of DNA. In our cells DNA packaging similar to the warehouse jewelry. Otherwise it is impossible to put a DNA helix with a length of two meters in one small cell nucleus.
DNA strand is wound in a turn and a half on the many "beads" called nucleosomes. These nucleosome, in turn, consist of several special proteins, the histones.
Histones have "tails" — the protein build-up that can be extended or shortened by special enzymes. The length of such "tail" directly affects the level of gene activity near it.
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Figure 5. X-ray crystal structure of nucleosome. Histones are shown in yellow, red, blue and green colors.
New Zealand scientists Gluckman P. and M. Hanson was able to formulate a logical explanation of the relationship of the amount of food during pregnancy mother health of the child. In 2004, the journal Science published their paper in which they articulated"a hypothesis of inconsistency" (mismatch hypothesis).
In accordance with her evolving body on an epigenetic level can occur anticipatory adaptation to environmental conditions that are expected after birth. If forecast confirmed — this increases the chances of the organism for survival in a world where he will live, if not, the adaptation becomes maladaptation, that is, disease.
For example, if during fetal development the fetus receives insufficient food, it occur the metabolic restructuring aimed at conservation of food resources for the future, "rainy day".
If after the birth of food is really small, it helps the organism survive. If the world goes the man, is more prosperous than expected, so the "Thrifty" nature of the metabolism can lead to obesity and diabetes of the 2nd type in the later stages of life. This variant today, we most often observe.
Overall, we can confidently say that pregnancy and the first months of life is the most important in the life of all mammals, including man. All the data available today say that it was during this period laid all the foundations of not only physical but also mental health. And the impact of this initial period of life so great that does not disappear till old age, forming — one way or another — the fate of man.
As aptly put by the German neuroscientist Peter Spork, «in advanced years on our health at times is much stronger affected by the diet of our mothers during pregnancy than food in the current moment of life". It's hard to believe, but the facts say directly about it.
Epigenetics has helped to make a very important conclusion: from what mom ate during pregnancy, in what psychological state she was in and how much time was given to the baby in the first years after birth, will depend on literally the whole future life of the child.At this time the Foundation is laid for all.
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Figure 6. Casinovega methylation of DNA bases.Scheme of methylated cytosine. Green oval with strelyayte the main enzyme of methylation — DNA-methyltransferase (DNMT), red circle — methyl group (—CH3).
The most studied mechanism of epigenetic regulation of gene activity is the methylation process that is to add a methyl group (one carbon atom and three hydrogen atoms —CH3) to casinowin the DNA bases within a CpG dinucleotide (Fig. 6).
It is already known that DNA methylation in eukaryotes is species-specific, and invertebrates methylation degree of the genome is very small in comparison with vertebrates and plants. The Foundation for understanding the functions of methylation was founded half a century ago by Professor of Moscow state University B. F. by Vanushina and his colleagues.
While often thought (and quite correctly) that the methylation "turns off" the gene, not allowing regulatory proteins to bind to DNA were detected and the opposite phenomenon. Sometimes DNA methylation acts as a mandatory condition of interaction with proteins has been described special m5CрG-binding proteins.
DNA methylation has the greatest practical value of all the epigenetic mechanisms, since it is directly related to diet, emotional status, brain activity and other factors.
So it's worth sharing in detail. And we start with the diet.
Today we know that many food products contain components that in some way affect epigenetic processes. Almost all women know that during pregnancy it is very important to consume enough folic acid.
Epigenetics helps to understand the critical importance of this acid in the diet: it's all about the DNA methylation. Folic acid along with vitamin B12 and the amino acid methionine is a donor ("supplier") methyl groups necessary for normal methylation.
Methylation is directly involved in many processes related to the development and formation of all organs and systems of the child: and the inactivation of the X chromosome in the embryo, and genomic imprinting, and cellular differentiation. Respectively, taking folic acid, the expectant mother has a good chance to bear a healthy child without disabilities.
Vitamin B12 and methionine it is almost impossible to obtain from a vegetarian diet as they are contained mainly in animal products. And a deficiency of vitamin B12 and methionine caused an unloading diet the pregnant woman can have for a child in the most unpleasant consequences.
Not so long ago it was discovered that the lack in the diet of these two substances, and also folic acid, may cause violations of the differences of chromosomes in the fetus. And this greatly increases the risk of having a child with down syndrome that is usually considered to be a simple tragic accident. In light of these facts, the responsibility of parents is greatly increased, and attribute it to accident now will be difficult.
It is also known that malnutrition and stress during pregnancy change in the "worse" the concentration of a number of hormones in the organisms of mother and fetus: glucocorticoids, catecholamines, insulin, growth hubbub. because Of this the embryo, there have been negative epigenetic changes (chromatin remodeling) in the cells of the hypothalamus and pituitary gland.
Than it is fraught? The fact that the baby will be born with a distorted function of the hypothalamic-pituitary regulatory system. Because of this, it would be worse to cope with stress of various nature: infection, physical and mental stress etc. it is clear that, under nourished and experiencing during pregnancy, the mother does of their unborn child vulnerable from all sides, loser.
The plasticity of the epigenome: dangers and opportunities
Turn out, that as well as stress and malnutrition, the health of the fetus can influence many substances that distort the normal processes of hormonal regulation (rice. 7). They got the name "endocrine disruptors" (destroyers).
These substances typically have an artificial nature: humanity gets them industrially for their needs. The most striking negative example, perhaps, is bisphenol a which for many years used as a hardener in the manufacture of plastic products.
It is contained in all plastic containers used today in the food industry: plastic bottles for water and drinks, food containers and much more. Bisphenol a is present in cans of canned food and drinks (they line the inner layer of cans), and also in dental fillings.
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Figure 7. Molecular components for the development of deviations under the influence of "endocrine disruptors": bisphenol-A (A) phthalates and (B).
The negative impact of even small concentrations of bisphenol A are many and varied, and the spread of it is that today it is almost impossible to find someone without bisphenol A in the body. It consistently found not only in blood but also in breast milk and cord blood of pregnant women.
Moreover, in the amniotic fluid (the fluid surrounding the embryo) concentration of bisphenol A is several times higher than its content in the mother's serum. In 2003-2004 by American researchers of the Center for control and prevention of diseases were obtained such results the prevalence of bisphenol A: from 2517 surveyed people from 92% in the urine contained BPA, and its concentration was significantly higher in children and adolescents who have ill-defined "sewage system" of the body.
It is obvious that, one way or another, as a result of the contact of food with plastic in some part of the BPA gets into the human body. The consequences of such "enrichment" are now under active study. But the disturbing facts emerge.
So, biologists from the medical school of Harvard Katherine Rakovski and her colleagues — discovered the ability of bisphenol A to slow down the maturation of the egg and thereby lead to infertility. BPA strongly increased the frequency of chromosomal abnormalities in eggs. The scientists ' conclusion was unambiguous: "As a contact with this stuff is happening everywhere, doctors need to know that bisphenol a can cause significant disruptions in the reproductive system."
Their colleagues from Columbia University in experiments with animals revealed another disturbing fact. They discovered the ability of bisphenol A to erase differences between the sexes and to encourage the birth of offspring with homosexual tendencies. Under the influence of BPA disrupted normal methylation of the genes encoding the receptors for the estrogens — female hormones.
This mouse males were born with a "female" character — docile and calm. Was no difference in the behavior of males and females. Professor F. Champaign and his colleagues had to say: «We have shown that exposure to low doses of bisphenol A causes lasting epigenetic abnormalities in the brain, which probably underlies the strong effects of bisphenol A on brain function and behavior, especially in relation to sexual differences".
Other studies show that bisphenol a has a very strong estrogenic activity (no wonder it is called "ubiquitous xenoestrogens") and is able to change during embryo development profile of methylation, and hence the activity of some genes (e.g., Hoxa10).
The implications of this for human health can be very unfavorable in adulthood increases the risk of certain diseases (obesity, diabetes, disorders of reproduction, etc.).
But fortunately, there are opposite examples. It is known that regular consumption of green tea may reduce the risk of cancer because it contains a substance epigallocatechin-3-gallate, which can activate genes — suppressors (suppressors) of tumor growth, dimethylurea their DNA.
Very popular in recent years, a modulator of epigenetic processes is genistein, contained in soy products. Many researchers have directly linked the content of soybeans in the diet of people in Asian countries with their lower susceptibility to some age-related disease.
Character is destiny?
Epigenetics also helped to understand why some people differ in psychological resilience and optimism, while others are prone to panic and depression. As is usual in the scientific world, first experiments were conducted with animals.
This series of works became widely known and the name "licking and grooming" (licking and grooming). A canadian biologist from McGill University — Michael Mini and his colleagues — began to study the influence of maternal care in rats in the first months of life of offspring. Dividing the rats into two groups, they took one part of the brood from their mothers immediately after birth. Not receiving maternal care in the form of licking, these rats all the polls grew "inadequate": the nervous, unsociable, aggressive and cowardly.
All calves in the group receiving maternal care in full volume, it evolved as befits rats: a robust, well-intelligent and socially active. What is the reason for such striking differences? Why maternal care has had a decisive influence on the development of mental characteristics in the offspring?DNA analysis helped answer these questions.
Examining the DNA of rats, scientists found that pups that were not licked mother has been a negative epigenetic changes in the brain area called the hippocampus. In the hippocampus was reduced number of receptors for stress hormones. And because of that, there was an inadequate response of the nervous system to external stimuli: pituitary glands were commanded to excessive production of stress hormones.In other words, those situations that were transferred safely normal rats, the offspring that have not received maternal care, inappropriately caused a lot of stress.
As it turned out, all of the above exactly suited to human development. There have been numerous studies of children who in early childhood were deprived of parental care or exposed to any violence. All of these children without exception grew up then with some distorted function in the nervous system.
And these distortions were epigeneticist enshrined in brain cells. All these children were peculiar inadequate response even for weak stimuli that are normally perceived prosperous children. All this formed in adulthood, a tendency to alcoholism, drug addiction, suicide and other inappropriate actions.
That's why the first years after birth are crucial in shaping social behavior and lay all the foundations of nature.How much time parents paid her baby in this period will depend on all his future: whether he is mentally stable, sociable, and successful or prone to depression and disorders.
It is obvious that the influence of the epigenome extends to processes associated with aging. With age one can observe a General decrease of methylation, including the enigmatic fragments of the genome, which make up almost half of all DNA sequences — mobile genetic elements (TES).
They were discovered half a century ago by Nobel laureate Barbara McClintock as sequences capable — in contrast to conventional genes — an amazing way to navigate through DNA. Needless activities with age due to demethylation of the IGE destabilisateur genome, causing unwanted chromosome rearrangements.
As we age, become distinct changes in the methylation of genes associated with age-related diseases: atherosclerosis, hypertension, diabetes, Alzheimer's, etc. in addition, it was found a direct link changes in the epigenome with the production of reactive oxygen species, as well as a function of one protein, which attracted great attention gerontologists: protein p66Shc, named by academician V. P. Skulachev "mediate programmed death of an organism". And because knowledge of epigenetic bases of age-related changes can bring us a substantial advantage in the struggle for life extension and healthy ageing.
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Results and prospects
The study of epigenetic mechanisms has helped to understand a very important truth: human destiny is formed for the most part not astrological forecasts, and the behavior of the person and his parents. Epigenetics clearly shows that much in life depends on us and in our forces to change life for the better.
Epigenetics also blurs the boundaries between man and the environment. Obviously, nobody can feel safe yet practiced large-scale use of hazardous chemicals.
The pesticides vinclozolin and Methoxychlor, used in agriculture and acting as endocrine disruptors, mercury from industrial waste and decomposing bisphenol A from plastic seep into the ground and into the water of rivers and seas. And then, along with food and water enter the human body. And it is a real threat to humanity.
But there is good news. In contrast with relatively stable genetic information, epigenetic "marks" under certain conditions can be reversible.
And it allows to develop fundamentally new strategies and methods to combat the most common diseases: methods, aimed at removing those epigenetic modifications that arose from the influence of adverse factors.
Not by chance this century some scholars have called the age of epigenetics. In the study of the history of natural Sciences, biology and genetics in particular, one might get the impression that in previous years was a great preparatory step, the accumulation of forces before the discovery is really an extremely important matter. And probably today we stand on the threshold of these discoveries.