Epigenetic modification. Epigenetics: mutations without changing DNA

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 heritable changes in gene activity during the development of an organism or cell division.

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

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

Structure of the human genome

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

The 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 about the structure of ribonucleic acid (RNA) and protein in the human body. The structures that convey hereditary information are called coding sequences. The Genome Project produced data that estimated the human genome to contain more than 30,000 genes. Currently, due to the emergence of new mass spectrometry results, 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 each - X or Y.

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

Both chains are held together by four bases: adenine (A), cytosine (C), guanine (G) and thiamine (T). Moreover, the base A on one chain can only connect to the base T on another chain, and similarly, the base G can connect to the base C. This is called the principle of base pairing. In other variants, pairing disrupts the entire integrity of the DNA.

DNA exists in an intimate complex with specialized proteins, and together they make up chromatin.

Histones are nucleoproteins that are the main constituents of chromatin. They are characterized by the formation of new substances by joining two structural elements into a complex (dimer), which is a feature for subsequent epigenetic modification and regulation.

DNA, which stores genetic information, self-reproduces (doubles) with each cell division, that is, it makes exact copies of itself (replication). During cell division, the bonds between the two strands of the DNA double helix are broken and the strands of the helix are separated. Then a daughter strand of DNA is built on each of them. As a result, the DNA molecule doubles and daughter cells are formed.

DNA serves as a template on which the synthesis of various RNAs (transcription) occurs. This process (replication and transcription) takes place in the cell nucleus and begins with a region of the gene called the promoter, where protein complexes bind to copy DNA 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 currently known that protein-coding regions of the human gene (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. The identified gene regions that do not code for proteins are called introns.

The first copy of mRNA produced from DNA contains the entire set of exons and introns. After this, specialized protein complexes remove all intron sequences and join exons together. This editing process is called splicing.

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

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

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. As knowledge accumulates, it becomes clear that in the genome itself there are multiple regulatory elements that control the functioning of genes. This is now confirmed by 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 that is not associated with changes in the primary structure of their DNA. Epigenetic changes are aimed at adapting the body 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.

Genetic traits are fixed indefinitely until a mutation occurs in a gene. Epigenetic modifications are usually reflected 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 modification of the genetic apparatus, i.e. 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 transport into the cytoplasm, during the selection of mRNA in the cytoplasm for translation on ribosomes, destabilization of certain types of mRNA in the cytoplasm, selective activation, inactivation of protein molecules after their synthesis.

The collection of epigenetic markers represents the epigenome. Epigenetic transformations can influence 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. sections of DNA that can move within the genome, as well as in the exchange of genetic material in chromosomes.

Epigenetic mechanisms are involved in genomic imprinting, a process in which the expression of certain genes occurs 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 ensure the initiation of processes in chromatin through histone modifications and DNA methylation. Over the past two decades, ideas about the mechanisms of transcription regulation in eukaryotes 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, which initiate the synthesis of messenger RNA. Histones and non-histone proteins played the role of a passive packaging structure to ensure compact packaging of DNA in the nucleus.

Subsequent studies demonstrated the role of histones in the regulation of translation. The so-called histone code was discovered, i.e., a modification of histones that is different in different regions of the genome. Modified histone codes can lead to gene activation and repression.

Various parts of the genome structure are subject to 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 them.

DNA methylation

In mammals, DNA methylation (an epigenetic mechanism) was studied earlier than others. It has been shown to correlate with gene repression. Experimental data show that DNA methylation is a protective 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, and inactivation of the X chromosome. Methyl groups disrupt DNA-protein interactions, preventing the binding of transcription factors. DNA methylation affects chromatin structure and blocks transcriptional repressors.

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

The methylation profile—activation or inhibition—changes 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 transient elements, viral and other repetitive sequences.

DNA methylation occurs through a reversible chemical reaction of the nitrogenous base, cytosine, resulting in the addition of a CH3 methyl group to the carbon to form methylcytosine. This process is catalyzed by DNA methyltransferase enzymes. Methylation of cytosine requires guanine, resulting in the formation of two nucleotides separated by a phosphate (CpG).

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

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

DNA methylation has a profound impact on gene expression and ultimately on the function of cells, tissues, and the body as a whole. A direct relationship has been 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 to cytosine independently 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, malignancies, and other diseases.

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

Histone acetylation

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

Histone acetylation and deacetylation enzymes (acetyltransferases) play a role during transcription. These enzymes catalyze the acetylation of local histones. Histone deacetylases repress transcription.

The effect of acetylation is the weakening of the bond between DNA and histones due to a change in charge, resulting in chromatin becoming accessible to transcription factors.

Acetylation is the addition of a chemical acetyl group (the amino acid lysine) to a free site on the histone. Like DNA methylation, lysine acetylation is an epigenetic mechanism for altering gene expression without affecting the original gene sequence. The pattern according to which modifications of nuclear proteins occur came 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 of genetic diseases, aging, DNA repair, replication, and translation. If histone modifications benefit the cell, 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 with the help of protein kinases.

Genes are under the control of phosphorylatable transcription factors, including genes that regulate cell proliferation. With such modifications, structural changes occur in chromosomal protein molecules, which 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, etc., which can attach via covalent bonds to the amino side 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 stimulating these changes, they disappear. The transfer of epigenetic information occurs during 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, which include antisense RNA (aRNA), microRNA (miRNA) and small interfering RNA (siRNA), are responsible for this function.

The mechanism of action of different regulatory RNAs is similar and consists in suppressing gene expression, which is realized through the complementary addition of regulatory RNA to mRNA, forming a double-stranded molecule (dsRNA). The formation of dsRNA itself 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 phenomenon of RNA interference may manifest itself - the Dicer enzyme, having detected double-stranded RNA in the cell, “cuts” it into fragments. One of the chains of such a fragment (siRNA) is bound by the RISC (RNA-induced silencing complex) protein complex.

As a result of RISC activity, a single-stranded RNA fragment binds to the complementary sequence of an mRNA molecule and causes the mRNA to be cut 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 and complement the “classical” scheme of gene regulation.

Genomic imprinting

A person has two copies of each gene, one inherited from the mother and the other from the father. Both copies of each gene have the potential to be active in any cell. Genomic imprinting is the 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 that is 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 primarily encode factors that regulate embryonic and neonatal growth.

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

Prions

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

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

Initially, prions were discovered as infectious agents of a new type, but now it is believed that they represent a general biological phenomenon and are carriers of a new type of information stored in the conformation of a protein. The prion phenomenon underlies epigenetic inheritance and 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. Disruption of epigenetic regulation mechanisms is directly or indirectly associated with many diseases.

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

In diseases of gene imprinting, monoallelic expression is observed in the chromosome loci of one of the parents. The cause is point mutations in genes that are differentially expressed depending on 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 symptoms of which are microbrachycephaly, enlarged lower jaw, protruding tongue, macrostomia, sparse teeth, hypopigmentation; Beckwitt-Wiedemann syndrome (methylation disorder in the short arm of chromosome 11), manifested by the classic triad, including macrosomia, omphalocele, macroglossia, etc.

The most important factors influencing the epigenome include 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.

Diseases where disruption of gene regulation is part of the pathogenesis include some types of tumors, diabetes mellitus, obesity, bronchial asthma, various degenerative and other diseases.

The epigone in cancer is characterized by global changes in DNA methylation, histone modification, as well as changes 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 regions of heterochromatin.

Thus, in 19% of cases of hypernephroid kidney tumors, the DNA of CpG islands 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 acetylation levels, the weaker the gene expression.

At present, antitumor drugs based on suppressing the activity of DNA methyltransferases have already been developed and put into practice, which leads to a decrease in DNA methylation, activation of tumor suppressor genes and a slowdown in the proliferation of tumor cells. Thus, for the treatment of myelodysplastic syndrome, the drugs decitabine (Decitabine) and azacitidine (Azacitidine) are used in complex therapy. Since 2015, Panibinostat, a histone deacytylase inhibitor, has been used in combination with classical chemotherapy to treat multiple myeloma. These drugs, according to clinical studies, 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 the action of environmental factors on the cell. The so-called “thrifty phenotype hypothesis” plays a role in the development of type 2 diabetes mellitus and obesity, according to which a lack of nutrients during embryonic development leads to the development of a pathological phenotype. In animal models, a DNA region (Pdx1 locus) was identified in which, under the influence of malnutrition, the level of histone acetylation decreased, while a slowdown in the division and impaired differentiation of B-cells of the islets of Langerhans and the development of a condition similar to type 2 diabetes mellitus 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 modifications of histones, etc.), such as chromatin immunoprecipitation (CHIP), flow cytometry and laser scanning, which gives reason to believe that biomarkers will be identified in the near future for the study of neurodegenerative diseases, rare, multifactorial diseases and malignant neoplasms and introduced as laboratory diagnostic methods.

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

Literature

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

Federal State Budgetary Educational Institution of Russian National Research University named after. N. I. Pirogova, Ministry of Health of the Russian Federation, Moscow

An organism with its environment during the formation of a phenotype. She studies the mechanisms by which, on the basis of genetic information contained in one cell (zygote), due to different gene expression 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 possibility of non-genomic inheritance is allowed as an adaptive response to environmental changes, which contradicts the currently dominant genocentric paradigm.

Examples

One example of epigenetic changes in eukaryotes is the process of cell differentiation. During morphogenesis, totipotent stem cells form the various pluripotent cell lineages of the embryo, which in turn give rise to fully differentiated cells. In other words, one fertilized egg - the zygote - differentiates into various 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 voles. In the fall, before cold weather, they are born with longer and thicker hair than in the spring, although the intrauterine development of “spring” and “autumn” mice occurs under almost identical conditions (temperature, day length, humidity, etc.). Studies have shown that the signal that triggers epigenetic changes leading to an increase in hair length is a change in the gradient of melatonin concentration in the blood (it decreases in the spring and increases in the fall). Thus, epigenetic adaptive changes (increase in hair length) are induced even before the onset of cold weather, adaptation to which is beneficial for the organism.

Etymology and definitions

The term "epigenetics" (as well as "epigenetic landscape") was proposed by Conrad 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 known, so he used it as a conceptual model for how genes might interact with their environment to produce 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, other than the DNA sequence itself.

The modern use of the word in scientific discourse is more narrow. The Greek prefix epi- in the word implies factors that act “over” or “in addition to” genetic factors, meaning epigenetic factors act in addition to or in addition to traditional molecular factors of heredity.

The similarity to 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 overall epigenetic state of the cell. The metaphor of "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 refers to a change in the normal epigenome caused by sporadic factors, transmitted over a number of cell generations.

Molecular basis of epigenetics

The molecular basis of epigenetics is quite complex, although 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 the genes necessary for their specific activities. A special feature of epigenetic changes is that they persist through cell division. It is known that most epigenetic changes occur only within the lifetime of a single 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 another. This raises the question, can epigenetic changes in an organism actually change the basic structure of its DNA? (See Evolution).

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

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

Mechanisms

DNA methylation and chromatin remodeling

Epigenetic factors influence the expression activity of certain genes at several levels, leading to changes in the phenotype of a cell or organism. One of the mechanisms of this influence is chromatin remodeling. Chromatin is a complex of DNA with histone proteins: DNA is wound onto histone proteins, which are represented by spherical structures (nucleosomes), resulting in its compaction in the nucleus. 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 for DNA. This is achieved in two ways described below.

DNA methylation

The most well studied epigenetic mechanism to date is methylation of cytosine DNA bases. Intensive research into the role of methylation in the regulation of genetic expression, including during aging, began back in the 70s of the last century with the pioneering work of B. F. Vanyushin and G. D. Berdyshev et al. The process of DNA methylation involves the addition of a methyl group to cytosine as part of a CpG dinucleotide at position C5 of the cytosine ring. DNA methylation is mainly characteristic of 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 process of DNA methylation. It is assumed that DNMT3a and DNMT3b are de novo methyltransferases that form the DNA methylation pattern at early stages of development, and DNMT1 carries out DNA methylation at later stages of the life of the organism. The function of methylation is to activate/inactivate a gene. In most cases, methylation leads to suppression of gene activity, especially when its promoter regions are methylated, and demethylation leads to its activation. It has been shown that even minor changes in the degree of DNA methylation can significantly change the level of genetic expression.

Histone modifications

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

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

The mechanism of reproduction of epigenetic marks has been better 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 the cytosine on only one DNA strand is methylated), it methylates the cytosine on the second strand at the same site.

Prions

MicroRNA

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

Meaning

Epigenetic inheritance in somatic cells plays a critical 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 different functions. It is epigenetic factors that provide “cellular memory”.

Medicine

Both genetic and epigenetic phenomena have a significant impact on human health. There are several known diseases that arise due to impaired gene methylation, as well as due to hemizygosity for a gene subject to genomic imprinting. For many organisms, a connection between histone acetylation/deacetylation activity and lifespan has been proven. Perhaps these same processes affect human life expectancy.

Evolution

Although epigenetics is primarily considered 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 can be targeted (adaptive). Since most of them disappear after a few generations, they can only be temporary adaptations. The possibility of epigenetics influencing the frequency of mutations in a particular gene is also being actively discussed. The APOBEC/AID family of cytosine deaminase proteins has been shown to be 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, a phenomenon in which the same genes have different methylation patterns depending on which sex parent they came from. The most famous cases of diseases associated with imprinting 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 and co-authors found that grandchildren (but not granddaughters) of men who were exposed to famine in Sweden in the 19th century were less likely to have cardiovascular disease but more likely to have diabetes, which the author suggests is an example epigenetic inheritance.

Cancer and developmental disorders

Many substances have the properties of epigenetic carcinogens: they lead to an increase in the incidence of tumors without exhibiting a mutagenic effect (for example: diethylstilbestrol arsenite, hexachlorobenzene, and nickel compounds). Many teratogens, in particular diethylstilbestrol, have specific effects 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. Gene activity in prostate cancer can be influenced by diet and lifestyle.

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 of the researchers who initiated the funding, epigenetics may play a larger role in the treatment of human diseases than genetics.

Epigenome and aging

In recent years, a growing body of evidence has accumulated that epigenetic processes play an important role in later life. In particular, widespread changes in methylation patterns occur with aging. It is assumed that these processes are under genetic control. Typically, the greatest number 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 was found in cultured lymphocytes from mice, hamsters and humans. It is systematic, but 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, found that 23 of these loci undergo hypermethylation and 6 hypomethylation with age, and Similar changes in methylation patterns were also detected in other tissues: pancreas, lungs and esophagus. Severe epigenetic distortions have been identified in patients with Hutchinson-Gilford progyria.

It is assumed that demethylation with age leads to chromosomal rearrangements through the activation of mobile genetic elements (MGEs), which are usually suppressed by DNA methylation (Barbot et al., 2002; Bennett-Baker, 2003). Systematic age-related decline in methylation levels may, at least in part, be responsible for many complex diseases that cannot be explained using classical genetic concepts. Another process that occurs in ontogenesis in parallel with demethylation and affects the processes of epigenetic regulation is chromatin condensation (heterochromatinization), leading to a decrease in genetic activity with age. In a number of studies, age-dependent epigenetic changes have also been demonstrated in germ cells; the direction of these changes appears 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

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In recent years, medical science has increasingly shifted its attention from studying the genetic code to the mysterious mechanisms by which DNA realizes its potential: it is packaged and interacts with proteins in our cells.

The so-called epigenetic factors are heritable, reversible and play a huge role in preserving the health of entire generations.

Epigenetic changes in a cell can trigger cancer, neurological and mental diseases, autoimmune disorders - it is not surprising that epigenetics attracts the attention of doctors and researchers from various fields.

It is not enough that your genes encode the correct sequence of nucleotides. The expression of each gene is an incredibly complex process that requires perfect coordination of the actions of several participating molecules.

Epigenetics poses additional challenges for medicine and science that we are only beginning to understand.

Every cell in our body (with few exceptions) contains the same DNA, donated by our parents. However, not all parts of DNA can be active at the same time. Some genes work in liver cells, others in skin cells, and others in nerve cells - which is why our cells are strikingly different from each other and have their own specialization.

Epigenetic mechanisms ensure that a cell of a certain type will operate with code unique to that type.

Throughout human life, certain genes can “sleep” or suddenly become activated. These obscure changes are influenced by billions of life events - moving to a new area, divorcing your wife, going to the gym, a hangover or a spoiled sandwich. Almost all events in life, big and small, can affect the activity of certain genes within us.

Definition of epigenetics

Epigenetic changes are heritable changes in gene expression and cell phenotype that do not affect the DNA sequence itself. The phenotype is understood as the entire set of characteristics of a cell (organism) - in our case, this is the structure of bone tissue, biochemical processes, intelligence and behavior, skin tone and eye color, etc.

Of course, the phenotype of an organism depends on its genetic code. But the further scientists delved into the issues of epigenetics, the more obvious it became that some characteristics of the body are inherited through generations without changes in the genetic code (mutations).

For many, this was a revelation: the body can change without changing genes, and pass on these new traits to descendants.

Epigenetic research in recent years has proven that environmental factors - living among smokers, constant stress, poor diet - can lead to serious disruptions in the functioning of genes (but not in their structure), and that these disruptions are easily transmitted to future generations. The good news is that they are reversible, and in some Nth generation they can dissolve without a trace.

To better understand the power of epigenetics, let's imagine our lives as a long movie.

Our cells are actors and actresses, and our DNA is a pre-prepared script in which each word (gene) gives the necessary commands to the cast. In this film, epigenetics is the director. The script may be the same, but the director has the power to remove certain scenes and bits of dialogue. So in life, epigenetics decides what and how every cell of our huge body will say.

Epigenetics and health

The most studied aspect of epigenetics is methylation. This is the process of adding methyl (CH3-) groups to DNA.

Typically, methylation affects gene transcription—the copying of DNA into RNA, or the first step in DNA replication.

A 1969 study was the first to show that DNA methylation can alter an individual's long-term memory. Since then, the role of methylation in the development of numerous diseases has become better understood.

Immune system diseases

Other scientists are confident that DNA methylation is the true cause of the development of rheumatoid arthritis.

Neuropsychiatric diseases

The role of DNA methylation in the development of Alzheimer's disease has already been practically proven. A large study has found that even in the absence of clinical symptoms, genes in nerve cells in patients prone to Alzheimer's disease are methylated differently than in normal brains.

The theory about the role of methylation in the development of autism has been proposed for a long time. Numerous autopsies examining the brains of sick people confirm that their cells do not have enough protein MECP2 (methyl-CpG-binding protein 2). This is an extremely important substance that binds and activates methylated genes. In the absence of MECP2, brain function is impaired.

Oncological diseases

In 1983, cancer became the first human disease to be linked to epigenetics. Then scientists discovered that colorectal cancer cells are much less methylated than normal intestinal cells. The lack of methyl groups leads to instability in chromosomes, and oncogenesis starts. On the other hand, an excess of methyl groups in DNA “puts to sleep” some genes responsible for suppressing cancer.

Since epigenetic changes are reversible, further research has paved the way for innovative cancer therapy.

In the Oxford journal Carcinogenesis in 2009, scientists wrote: “The fact that epigenetic changes, unlike genetic mutations, are potentially reversible and can be restored to normal makes epigenetic therapy a promising option.”

Epigenetics is still a young science, but thanks to the multifaceted impact of epigenetic changes on cells, its successes are already amazing. It is a pity that not earlier than in 30-40 years our descendants will be able to fully realize how much it means to the health of humanity.

: Master of Pharmacy and professional medical translator

Epigenetics is a relatively new branch of genetics that has been called one of the most important biological discoveries since the discovery of DNA. It used to be that the set of genes we are born with irreversibly determines our lives. However, it is now known that genes can be turned on or off, and can be expressed more or less under the influence of various lifestyle factors.

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

Epigenetics: Lifestyle changes are the key to changing genes

Epigenetics - a science that studies processes that lead to changes in gene activity without changing the DNA sequence. Simply put, epigenetics studies the effects 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 rebuild itself. However, the genes themselves need “instructions” by which they determine the necessary actions and the time for their implementation.

Epigenetic modifications are the very instructions.

There are several types of such modifications, but the two main ones are those affecting 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 light regulator (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.

The key to understanding the influence of external factors on gene activity was observing the lives of identical twins. Observations have shown how strong changes can be in the genes of such twins leading different lifestyles in different external conditions.

Identical twins are supposed to have "common" illnesses, 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.

The Secrets of Epigenetics: How Lifestyle Factors Affect Genes

Research in epigenetics has shown that only 5% of disease-associated gene mutations are completely deterministic; the remaining 95% can be influenced through nutrition, behavior and other environmental factors. The healthy lifestyle program allows you to change the activity of 4000 to 5000 different genes.

We are not simply 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 “genetic maps” nature has given you - what matters is what you do with them.

Epigenetics is in its infancy and much remains to be learned, but knowledge exists about the major lifestyle factors that influence gene expression.

1. Nutrition, sleep and exercise

It is not surprising that nutrition can influence the state of DNA. A diet rich in processed carbohydrates causes DNA to be attacked by high levels of glucose in the blood. On the other hand, DNA damage can be reversed by:

• sulforaphane (found in broccoli);
• curcumin (found 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. Gene expression (117) is positively affected by exercise.

1. Stress, relationships and even thoughts

Epigeneticists argue that it is not only “material” factors such as diet, sleep and exercise that influence genes. As it turns out, stress, relationships with people and your thoughts are also significant factors influencing 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; Moreover, the effect of such practice is visible after 8 hours of training;
• 400 scientific studies have shown that expressing gratitude, kindness, optimism and various techniques that engage the mind and body have a positive effect on gene expression;
• Lack of activity, poor nutrition, constant negative emotions, toxins and bad habits, as well as trauma and stress trigger negative epigenetic changes.

Durability of epigenetic changes and the future of epigenetics

One of the most exciting and controversial discoveries is that epigenetic changes are passed on to subsequent generations without changing the gene sequence. Dr. Mitchell Gaynor, author of The Gene Therapy Blueprint: Take Control of Your Genetic Destiny Through Nutrition and Lifestyle, believes that gene expression is also inherited.

Epigenetics, says Dr. Randy Jirtle, shows that we are also responsible for the integrity of our genome. Previously, we believed that everything depended on genes. Epigenetics allows us to understand that our behavior and habits can influence the expression of genes in future generations.

Epigenetics is a complex science that has enormous potential. Experts still have a lot of work to do to determine exactly what environmental factors influence our genes, how we can (and whether) we can reverse diseases or prevent them as effectively as possible.

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

One of the most daring and inspiring epigenetic hypotheses, that the activity of many genes is subject to external influence, is now being confirmed in many experiments in animal models. The researchers cautiously comment on their results, but do not rule out that Homo sapiens does not fully depend on heredity, which means it can purposefully influence it.

In the future, if scientists turn out to be right and they manage to find the keys to the mechanisms of gene control, humans will be able to control the physical processes occurring in the body. Aging may well be one of them.

In Fig. mechanism of RNA interference.

dsRNA molecules can be a hairpin RNA or two paired complementary strands of RNA.
Long dsRNA molecules are cut (processed) in the cell into short ones by the Dicer enzyme: one of its domains specifically binds 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 of 20-25 nucleotides in length (siRNA) is formed, and Dicer proceeds to the next cycle of cutting the dsRNA, binding to its newly formed end.

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

Other, as yet unknown, mechanisms are also possible.
The difference between epigenetic and genetic mechanisms of inheritance is their stability and 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 over a series of cell generations within the life of one organism. When they are transmitted to subsequent generations, they can reproduce for no more than 3-4 generations, and then, if the stimulus that induced them disappears, they gradually disappear.

What does this look like at the molecular level? Epigenetic markers, as these chemical complexes are usually called, are not located in the nucleotides that form the structural sequence of the DNA molecule, but they directly pick up certain signals?

Absolutely right. Epigenetic markers are indeed not IN the nucleotides, but ON them (methylation) or OUTSIDE them (acetylation of chromatin histones, microRNAs).
What happens when these markers are passed on to subsequent generations is best explained using the analogy of a Christmas tree. Passing from generation to generation, “toys” (epigenetic markers) are completely removed from it during the formation of a blastocyst (8-cell embryo), and then, during the process of 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 which has completely revolutionized our understanding of biology, has to do with epigenetic modifications acquired during the life of a given organism.

For example, if the body is under the influence of a certain influence (heat shock, fasting, etc.), a stable induction of epigenetic changes occurs (“buying a new toy”). As previously assumed, such epigenetic markers are completely erased during fertilization and embryo formation and, thus, are not passed on to offspring. It turned out that this was not the case. In a large number of studies in recent years, epigenetic changes induced by environmental stress in representatives of one generation were detected in representatives of 3-4 subsequent generations. This indicates the possibility of inheritance of acquired characteristics, which until recently was considered absolutely impossible.

What are the most important factors causing epigenetic changes?

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

But, in addition, there is evidence that the most “sensitive” period during which major epigenetic modifications are possible is periconceptual (the first two months after conception). It is possible that attempts at 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 embryonic development stage, some researchers are trying to correct it in adults.

For example, Min Ju Fan ( 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)) can activate tumor suppressor genes through DNA demethylation.

Currently, about a dozen drugs are already under development in the United States and Germany, the creation of which was based on the results of recent studies of epigenetics in the diagnosis of cancer.
What are the key questions 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 (“like a stage of ontogeny”). Research in this area has only begun in recent years, but if it is successful, humanity may have 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 we can 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 6 weeks, and a queen bee lives 6 years.
With complete genetic identity, they differ only in that the future queen bee is fed royal jelly for several days more during development than an ordinary worker bee.

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

During research in the 60s, it was shown that it decreases with age. But have scientists made any progress in answering the question: why is this happening?

There is a lot of work indicating that the characteristics and rate of aging depend on the conditions of early ontogenesis. Most associate this with the correction of epigenetic processes.

DNA methylation does indeed decrease with age; why this happens is not yet known. One version is that this is a consequence of adaptation, an attempt by the body to adapt to both external stress and internal “super stress” - aging.

It is possible that DNA “turned on” during age-related demethylation is an additional adaptive resource, one of the manifestations of the vitaukta process (as it was called by the outstanding gerontologist Vladimir Veniaminovich Frolkis) - 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 section of genes. So far, the most promising way to carry out such operations is biotechnological. But this is still an experimental direction and there are no major breakthroughs in it yet. Methylation is a more flexible process; it is easier to change, including with the help of pharmacological drugs. Is it possible to learn to control selectively? What else remains to be done for this?

Methylation is unlikely. It is non-specific, it affects everything “wholesale”. You can teach a monkey to hit the keys of a piano, and it will produce loud sounds from it, but it is unlikely to perform the “Moonlight Sonata”. Although there are examples where, 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 normal coat color occurred in these mice because the “defective” gene was “turned off” due to methylation.

But it is possible to selectively influence gene expression, and interfering RNAs, which act highly specifically, only on “their own” ones, are excellent for this. Such work is already being carried out.

For example, American researchers recently transplanted human tumor cells into mice whose immune system was suppressed, which could freely multiply and metastasize in immunodeficient mice. Scientists were able to identify those expressed in metastasizing cells and, by synthesizing the corresponding 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 underlie various processes occurring in living organisms. What are they? What factors influence their formation? Are scientists able to decipher these signals?

Signals can be very different. During development and stress, these are signals primarily 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 heat shock protein genes (HSP70) in cell culture fields. In this case, this field, of course, does not act “energetically”, but is a kind of signal “trigger” that “starts” gene expression. There is still a lot of mystery here.

For example, recently opened bystander effect(“bystander effect”).
Briefly, its essence is this. When we irradiate a cell culture, they experience a wide range of reactions, from chromosomal aberrations to radioadaptive reactions (the ability to withstand high doses of radiation). But if we remove all the irradiated cells and transfer other, non-irradiated cells into the remaining nutrient medium, they will show the same reactions, although no one has irradiated them.

It is assumed that irradiated cells release certain epigenetic “signaling” factors into the environment, which cause similar changes in non-irradiated cells. No one knows yet what the nature of these factors is.

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

If a reliable technique for “epigenetic reprogramming” of somatic cells into stem cells is developed, this will certainly 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 our lives? For example, geneticists from the University of Melbourne, who studied the mechanisms of cellular memory, discovered that after receiving a one-time dose of sugar, the cell stores the corresponding chemical marker for several weeks.

There is even a special section on 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 formulas based on cow's milk, epigenetic changes occur in the cells of his body, which, fixed by the imprinting mechanism, lead over time to the onset of an autoimmune process in the beta cells of the pancreas and , as a consequence, type I diabetes.

In Fig. development of diabetes (the figure enlarges when clicked with the cursor). In autoimmune diseases such as type 1 diabetes, a person's immune system attacks his own organs and tissues.
Some 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.
(drawing from the magazine “IN THE WORLD OF SCIENCE”, July 2007 No. 7)

And inadequate (limited in the number of calories) nutrition during fetal development is a direct path to obesity in adulthood and type II diabetes.

Does this mean 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 believed.

What is the epigenetic component in the so-called genomic imprinting?

With genomic imprinting, the same gene appears phenotypically 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 is not expressed, whereas a gene inherited from the father is not methylated and is expressed.

The most actively studied is genomic imprinting 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 diseases themselves that 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” caused by their presence in the maternal or, conversely, paternal organisms. In other words, they carry the "epigenetic imprint" of the parent's sex. When present in the body of an ancestor of a certain sex, they are methylated (functionally repressed), and of another - demethylated (respectively, expressed), and in the same state are inherited by descendants, leading (or not leading) to the occurrence of certain diseases.

You have been studying the effects of radiation on the body. It is known that low doses of radiation have a positive effect on the lifespan of fruit flies fruit flies. Is it possible to train the human body with low doses of radiation? Alexander Mikhailovich Kuzin, expressed by him back in the 70s of the last century, doses that are approximately 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 mortality rate from it differs 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 your studies, you analyzed data on the dates of birth and death of 105 thousand Kiev residents who died between 1990 and 2000. What conclusions were 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 for those born in April-July. The differences between the minimum and maximum monthly averages turned out to be 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 largely depends on the season of the year in which he was born.

Is it possible to apply the information obtained?

What could be the recommendations? For example, should children be conceived in the spring (preferably in March) so that they are potentially long-lived? 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 capabilities. These studies demonstrate the futility of “applied” recommendations for having children during certain months of the year. But these works, of course, are a serious reason for further scientific research into the mechanisms that determine “programming,” as well as the search for means of targeted correction of these mechanisms in order to prolong life in the future.

One of the pioneers of epigenetics in Russia, Moscow State University professor Boris Vanyushin, in his work “Materialization of epigenetics or Small changes with big consequences,” wrote that the last century was the century of genetics, and the current one is the century of epigenetics.

What allows us to evaluate 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 that control the development and functioning of the body will lead to a revolution in biology and medicine.

For example, a number of studies have already been able to identify typical patterns in such drawings. Based on them, doctors can diagnose the formation of cancer at an early stage.
But is such a project feasible?

Yes, of course, although it is very expensive and can hardly be implemented during a crisis. But in the long term - 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 talked about this. But if every cell of an organism contains the same genome, then each type of cell has its own epigenome, and accordingly 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.

This is why the Human Epigenome project is very difficult (although not hopeless) to implement.

He believes that the smallest phenomena can have a huge impact on a person’s life: “If the 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 all that serious?

Certainly. 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 can certainly have a significant impact on all aspects of people’s lives, from their 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, influence the expression of genes - A CONTRADICTION TO THE CENTRAL DOGMA OF MOLECULAR BIOLOGY, ACCORDING TO WHICH THE FLOW OF INFORMATION CAN ONLY GO FROM DNA TO PROTEINS, BUT NOT THE OVERSEAS.
Epigenetic changes induced in early ontogenesis can be recorded by the imprinting mechanism and change the entire subsequent fate of a person (including psychotype, metabolism, predisposition to diseases, etc.) - ZODIACAL ASTROLOGY.
The cause of evolution, in addition to random changes (mutations) selected by natural selection, are directed, adaptive changes (epimutations) - THE CONCEPT OF CREATIVE EVOLUTION by the French philosopher (Nobel laureate in literature, 1927) Henri BERGSON.
Epimutations can be transmitted from ancestors to descendants - INHERITANCE OF ACQUIRED CHARACTERISTICS, LAMARCHISM.

What pressing questions will need 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 functions of various organs of the body?

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

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

What is the role of epigenetic mechanisms in the aging process, is it possible to prolong life with their help?

Is it possible that the currently incomprehensible patterns of evolution of living systems (non-Darwinian evolution) are explained by the involvement of epigenetic processes?

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