Epigenetics: what controls our genetic code? Genetics and epigenetics: basic concepts Diseases of the immune system.

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 the 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 RNAs (aRNA), microRNAs (miRNAs) and small interfering RNAs (siRNAs), 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

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

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

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

4910 0

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

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 the 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

The DNA sequencing of the human genome and the genomes of many model organisms has generated considerable excitement in the biomedical community and among the general public over the past few years. These genetic blueprints, demonstrating the generally accepted rules of Mendelian inheritance, are now readily available for careful analysis, opening the door to greater understanding of human biology and disease. This knowledge also raises new hopes for new treatment strategies. However, many fundamental questions remain unanswered. For example, how does normal development occur, given that each cell has the same genetic information and yet follows its own specific developmental path with high temporal and spatial precision? How does a cell decide when to divide and differentiate and when to maintain its cellular identity, reacting and expressing itself according to its normal developmental program? Errors that occur in the above processes can lead to disease conditions such as cancer. Are these errors encoded in erroneous blueprints that we inherited from one or both parents, or are there other layers of regulatory information that were not correctly read and decoded?

In humans, genetic information (DNA) is organized into 23 pairs of chromosomes, consisting of approximately 25,000 genes. These chromosomes can be compared to libraries containing different sets of books that together provide instructions for the development of an entire human organism. The DNA nucleotide sequence of our genome consists of approximately (3 x 10 to the power of 9) bases, abbreviated in this sequence by the four letters A, C, G and T, which form certain words (genes), sentences, chapters and books. However, what dictates exactly when and in what order these different books should be read remains far from clear. The answer to this extraordinary challenge likely lies in understanding how cellular events are coordinated during normal and abnormal development.

If you add up all the chromosomes, the DNA molecule in higher eukaryotes is about 2 meters long and, therefore, must be maximally condensed - about 10,000 times - in order to fit into the cell nucleus - the compartment of the cell in which our genetic material is stored. Winding DNA onto spools of proteins, called histone proteins, provides an elegant solution to this packaging problem and gives rise to a polymer of repeating protein:DNA complexes known as chromatin. However, in the process of packaging DNA to better fit a limited space, the task becomes more complex - much in the same way as when stacking too many books on library shelves: it becomes harder and harder to find and read the book of choice, and thus an indexing system becomes necessary .

This indexing is provided by chromatin as a platform for genome organization. Chromatin is not homogeneous in its structure; it appears in a variety of packaging forms, from a fibril of highly condensed chromatin (known as heterochromatin) to a less compacted form where genes are typically expressed (known as euchromatin). Changes can be introduced into the underlying chromatin polymer by the inclusion of unusual histone proteins (known as histone variants), altered chromatin structures (known as chromatin remodeling), and the addition of chemical tags to the histone proteins themselves (known as covalent modifications). Moreover, the addition of a methyl group directly to a cytosine base (C) in the DNA template (known as DNA methylation) can create protein attachment sites to alter the state of chromatin or influence covalent modification of resident histones.

Recent data suggest that non-coding RNAs can “direct” the transition of specialized regions of the genome into more compact chromatin states. Thus, chromatin should be viewed as a dynamic polymer that can index the genome and amplify signals from the environment, ultimately determining which genes should be expressed and which should not.

Taken together, these regulatory capabilities endow chromatin with a genome-organizing principle known as “epigenetics.” In some cases, epigenetic indexing patterns appear to be inherited during cell division, thereby providing a cellular “memory” that can expand the potential for heritable information contained in the genetic (DNA) code. Thus, in the narrow sense of the word, epigenetics can be defined as changes in gene transcription caused by chromatin modulations that are not the result of changes in the nucleotide sequence of DNA.

This review introduces basic concepts related to chromatin and epigenetics, and discusses how epigenetic control may provide clues to some long-standing mysteries - such as cell identity, tumor growth, stem cell plasticity, regeneration and aging. As readers work their way through subsequent chapters, we encourage them to consider the wide range of experimental models that appear to have an epigenetic (non-DNA) basis. Expressed in mechanistic terms, understanding how epigenetics functions will likely have important and far-reaching implications for human biology and disease in this “post-genomic” era.

Perhaps the most comprehensive and at the same time accurate definition of epigenetics belongs to the outstanding English biologist, Nobel laureate Peter Medawar: “Genetics suggests, but epigenetics disposes.”

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

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

Mutation Control

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

A revolution in the genetic worldview occurred at the very end of the last century. A number of experimental data were obtained in several laboratories at once, which made geneticists think very hard. So, in 1998, Swiss researchers led by Renato Paro from the University of Basel conducted experiments with Drosophila flies, which, due to mutations, had yellow eyes. It was discovered that, under the influence of increased temperature, mutant Drosophila offspring were born not with yellow, but with red (as normal) eyes. One chromosomal element was activated in them, which changed their eye color.

To the surprise of the researchers, the red eye color remained in the descendants of these flies for another four generations, although they were no longer exposed to heat. That is, inheritance of acquired characteristics occurred. Scientists were forced to make a sensational conclusion: stress-induced epigenetic changes that do not affect the genome itself can be fixed and transmitted to future generations.

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

What can connect predisposition to diabetes and date of birth? New Zealand scientists Peter Gluckman and Mark Hanson managed to formulate a logical explanation for this paradox. They proposed the “mismatch hypothesis,” according to which “predictive” adaptation to the environmental conditions expected after birth can occur in a developing organism. If the prediction is confirmed, this increases the organism's chances of survival in the world where it will live. If not, adaptation becomes maladaptation, that is, a disease.

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

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

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

Destiny by inheritance

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

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

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

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

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

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

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

An analysis of their genome showed the absence of DNA methylation in precisely those areas where it ensures the preservation of good health. Thus, in elderly Dutch men whose mothers survived the famine, the methylation of the insulin-like growth factor (IGF) gene was noticeably reduced, which is why the amount of IGF in the blood increased. And this factor, as scientists well know, has an inverse relationship with life expectancy: the higher the level of IGF in the body, the shorter life.

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

The many faces of epigenetics

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

Genes are not a death sentence

In addition to stress and malnutrition, fetal health can be affected by numerous substances that interfere with normal hormonal regulation. They are called “endocrine disruptors” (destroyers). These substances, as a rule, are of an artificial nature: humanity obtains them industrially for their needs.

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

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

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

The study of epigenetic mechanisms has helped us understand an important truth: so much in life depends on ourselves. Unlike relatively stable genetic information, epigenetic “marks” can be reversible under certain conditions. This fact allows us to count on fundamentally new methods of combating common diseases, based on the elimination of those epigenetic modifications that arose in humans under the influence of unfavorable factors. The use of approaches aimed at correcting the epigenome opens up great prospects for us.