Epigenetics: How a way of life changes a genetic predisposition

Epigenetics: How a way of life changes a genetic predisposition

Chapter 1: Fundamentals of epigenetics: molecular mechanisms and genes regulation

Epigenetics, in its essence, is a study of hereditary changes in genes expression, which are not associated with changes in the sequence of DNA itself. This is the field of science that reveals the mechanisms through which the environment and lifestyle can affect how our genes are “expressed” – that is, how actively they participate in the synthesis of proteins that determine our characteristics and body functions.

1.1. DNA methylation: Silence for genes

DNA methylation is one of the most studied epigenetic mechanisms. It includes the accession of a methyl group (CH3) to cytosin, one of the four bases that make up DNA. This process usually occurs in CPG-fasteners-areas of DNA, cytosine-guanine rich in sequences. Methyling of CPG fasteners in the promoter areas of genes (regions regulating the beginning of transcription) often leads to genes repression.

• Enzymes participating in DNA methylating: DNA-methyltransferase (DNMTS) is a family of enzymes that catalyze the connection of the methyl group to cytosine. In mammals, the most studied DNMT1, DNMT3A and DNMT3B. DNMT1 plays the role of “supportive” methyltransferase, copying methylation patterns from the existing DNA thread for a new thread during replication. DNMT3A and DNMT3B install new methylation patterns and play a role in development.
• Methylaxation mechanism: DNA methylation can suppress the expression of genes in two main methods. Firstly, the methyl group directly prevents the binding of transcription factors (proteins required to launch transcription) with DNA. Secondly, methylated CPG-fasteners are attracted by proteins binding to methylated DNA (MBDS), which, in turn, recruit histondacilasis (HDACS) and other proteins that lead to chromatin condensation and transcription suppression.
• Examples of the influence of methylation:
  • Inactivation of the X-chromosomes: In women, one of the two X-chromosomes is inactivated to compensate for the double dose of X-chromosome genes. This process includes extensive methylation of an inactivated X-chromosome.
  • Genes imprinting: Some genes are expressed only from one parental allele (either from father or mother). This process is regulated by methylation and other epigenetic mechanisms.
  • Cancer development: Aberrant methylation, such as hypermethylization of tumor-soup genes and hypomethylation of oncogenes, plays an important role in the development of cancer.

1.2. Histonian modifications: regulating DNA availability

Histons are proteins around which DNA is wrapped, forming chromatin. Modifications of histones, such as acetylation, methylation, phosphorylation and killing, affect the structure of chromatin and, therefore, the availability of DNA for transcription factors and other proteins involved in the regulation of genes.

• Acetylation of histones: Acetylation of Lizin residues of histones, catalyzed histoneacetyltransferazes (Hats), is usually associated with genes activation. Acetylation neutralizes a positive charge of the sties, weakening the interaction between histones and negatively charged DNA, which leads to chromatin deconance and transcription relief.
• Tyiston methylation: The methylation of lysine and arginine residues of histones can be associated with both activation and the repression of genes, depending on which residue is methylated and how many methyl groups are added. For example, the H3K4ME3 methylation (methylation of trimethyl of lysine 4 histone H3) is usually associated with active transcription, while methylation H3K9ME3 and H3K27ME3 is associated with genes repression.
• Enzymes participating in histones modifications: In addition to HATS, acetyl groups are removed, and mononmethyltransferases (HMTS) add methyl groups. There are also histone-dodalasis (HDMS) that remove methyl groups. The balance of the activity of these enzymes determines the state of modifications of histones and, therefore, the expression of genes.
• Examples of the influence of histone modifications:
  • Regulation of cell differentiation: Histonian modifications play a key role in determining the fate of cells during development.
  • Memory formation: Epigenetic changes, including histone modifications, are involved in consolidation and maintenance of memory.
  • Development of neurodegenerative diseases: Aberrant modifications of histones are associated with the development of Alzheimer’s disease, Parkinson’s disease and other neurodegenerative diseases.

1.3. RNA interference: powerful genes expression regulator

RNA interference (RNAI) is a mechanism for regulating genes expression, mediated by small non-leading RNA, such as microrm (Mirna) and small interfering RNA (Sirna). These RNA molecules are associated with complementary sequences of the MRNA and either lead to MRNA degradation or block the broadcast, thereby suppressing the expression of the corresponding genes.

• MIRNORNK (MIRNA): Mirna is short (about 22 nucleotides) non-leading RNA that regulate the expression of genes by binding to the 3′-non-nested area (3′-UTR). The binding of Mirna with MRNA can lead to degradation of MRNU or blocked broadcasts. One Mirna can regulate the expression of hundreds of various MRNA, which makes Mirna powerful genes expression regulators.
• Small interfering RNA (sirna): Sirna is two -chain RNA, which are used by a cell to protect against viral infections and transposons. Sirna is associated with the RISC (RNA-induced SILENCING COMPLEX) complex, which then uses Sirna as a guide for the search and degradation of the MRNA with a complementary sequence. Sirna is also used in the laboratory for targeted suppression of genes expression.
• RNA interference mechanism: The process of RNA interference begins with the formation of pre-mirna or long double-tension RNA, which are then processed by the dicer enzyme in the cytoplasm. Dicer cuts pre-mirna or long double-tension RNA for short double-tension RNA (Mirna or Sirna). One of the Mirna or Sirna chains is loaded into the RISC complex. The RISC complex uses Mirna or Sirna as a guide for searching and binding to a complementary MRNA sequence. RISC binding to MRNA can lead to MRNA degradation or broadcasting.
• Examples of the influence of RNA interference:
  • Development and differentiation: Mirna play an important role in the regulation of the development and differentiation of cells.
  • Immune answer: RNA interference is involved in the regulation of the immune response and protection against viral infections.
  • Cancer development: Mirna’s aberrant expression is associated with cancer. Some Mirna act as oncogenes, while others act as tumor-soup genes.

1.4. Other epigenetic mechanisms: the role of chromatin and protein complexes

In addition to DNA methylation, modifications of histones and RNA interference, there are other epigenetic mechanisms that participate in the regulation of genes expression. These include:

• Reorganization chromatin: The structure of chromatin plays an important role in the regulation of genes expression. Compact chromatin (heterochromatin) is usually associated with genes repression, while deconced chromatin (euhromatin) is usually associated with active transcription. The reorganization of chromatin can occur under the influence of various factors, including modifications of histones and the binding of certain proteins with DNA.
• The role of non -pounding RNA: In addition to Mirna, there are other types of non -dodging RNA, such as long non -dodging RNA (LNCRNA), which are involved in the regulation of genes expression. LNCRNA can interact with DNA, RNA and proteins, forming complexes that regulate transcription, splashing and other processes.
• Protein complexes: Many protein complexes, such as chromatin remodeling complexes, participate in the regulation of genes expression. Chromatin remodeling complexes use ATP energy to change the structure of chromatin, making DNA more or less accessible to transcription factors.

1.5. Epigenetic heredity: transmission of epigenetic information

One of the most interesting and important aspects of epigenetics is the possibility of transmitting epigenetic information from one generation of cells to another (mitotic heredity) and even from one generation of organisms to another (transgeneration heredity).

• Mitotic heredity: Epigenetic changes, such as DNA methylation and modification of histones, can be copied and transferred to subsidiacs during cell division. For example, DNMT1 “copies” methylation patterns from the existing DNA thread for a new thread during replication.
• Transgenerative heredity: Transgenerative heredity is the transmission of epigenetic information from one generation of organisms to another through the embryo line (spermatozoa and eggs). For a long time it was believed that the epigenetic marks are “erased” during the development of the embryo line, but now evidence arises that some epigenetic changes can avoid washing and transmitted to the next generation. The mechanisms of transgenerational heredity have not been fully studied, but it is assumed that small RNAs and modifications of histones are involved in this process.
• The meaning of epigenetic heredity: Epigenetic heredity can play an important role in the adaptation of organisms to the environment and in the development of diseases. For example, studies have shown that the diet of a pregnant woman can affect epigenetic patterns in her offspring, which, in turn, can affect the risk of diseases, such as obesity and diabetes.

Chapter 2: The role of a lifestyle in the formation of an epigenetic landscape

Life has a deep effect on the epigenetic landscape of the body. Factors, such as diet, physical activity, smoking, alcohol use and toxins, can cause changes in DNA methylization, modifications of histones and expression of small RNA, which, in turn, affects the risk of various diseases.

2.1. Diet: the foundation of epigenetic health

Diet is one of the most powerful factors affecting the epigenetic landscape. The nutrients that we get from food are involved in the biochemical reactions necessary for DNA methylation, histone modifications and the synthesis of small RNA.

• Folic acid: Folic acid is a vitamin of group B necessary for DNA synthesis and DNA methylation. Folic acid deficiency can lead to DNA hypomethylation and increased risk of cancer and other diseases.
• Vitamin B12: Vitamin B12 is also necessary for DNA methylation. Vitamin B12 deficiency can lead to DNA hypomethylation and neurological disorders.
• Kholin: Kholin is a nutrient necessary for the synthesis of phosphatidylcholine, an important component of cell membranes. Kholin also participates in DNA methylation and histone synthesis.
• Betaine: Betain (trimethyllycin) is a derivative of choline that can participate in DNA methylation. Betain can be useful for improving the health of the liver and reduce the risk of developing cardiovascular diseases.
• Green tea (EGCG): Epagallokatekhin-3-Gallat (EGCG) is a polyphenol contained in green tea, which has antioxidant and anti-cancer properties. EGCG can affect DNA methylation and modifications of histones, inhibiting DNMTS and HDACS.
• Curcumin: Kurkumin is a polyphenol contained in Kurkum, which has anti -inflammatory and anti -cancer properties. Kurkumin can influence DNA methylation and modification of histones, inhibiting DNMTS and HDACS.
• Genisine: Genastin is an isoflavon contained in soy products that has antioxidant and anti -cancer properties. Genastin can affect DNA methylation and modifications of histones, inhibiting DNMTS and HDACS.
• The influence of the diet on development: Diet of the mother during pregnancy can have a deep effect on epigenetic patterns in her offspring, affecting the risk of developing diseases in further life. For example, a deficiency of folic acid during pregnancy can lead to defects in the nervous tube in newborns.

2.2. Physical activity: movement – life and epigenetic well -being

Physical activity has a positive effect on the epigenetic landscape, affecting DNA methylation, modification of histones and the expression of small RNA.

• Improving DNA methylation: Regular physical activity can improve DNA methylation patterns, reducing the risk of cancer and other diseases.
• Modifications of histones: Physical activity can affect the modification of histones, increasing acetylation of histones and improving DNA accessibility for transcription factors.
• Expression of small RNA: Physical activity can affect the expression of small RNA regulating glucose and lipid metabolism.
• Neurogenesis: Physical activity stimulates neurogenesis (the formation of new neurons) in the hippocampus, the area of ​​the brain that is responsible for memory and training. This process can be mediated by epigenetic changes.
• Reduction of risk of chronic diseases: Regular physical activity reduces the risk of developing chronic diseases, such as obesity, type 2 diabetes, cardiovascular diseases and some types of cancer. Part of this effect may be associated with epigenetic changes.

2.3. Smoking: epigenetic blow under the breath

Smoking has a negative impact on the epigenetic landscape, causing changes in DNA methylization, modifications of histones and expression of small RNA, which increases the risk of cancer, cardiovascular diseases and other diseases.

• DNA methylation: Smoking causes changes in DNA methylization, leading to hypomethylaxation of some genes and hypermethylization of other genes. These changes can contribute to the development of cancer.
• Modifications of histones: Smoking can affect the modification of histones, leading to changes in the structure of chromatin and genes expression.
• Expression of small RNA: Smoking can affect the expression of small RNA regulating inflammation and an immune response.
• The risk of cancer development: Smoking is the main risk factor for the development of lung cancer, laryngeal cancer, cancer of the oral cavity, esophagus cancer, bladder cancer and other types of cancer. Epigenetic changes caused by smoking play an important role in the development of these diseases.
• Pregnancy influence: Smoking during pregnancy has a negative effect on the development of the fetus, increasing the risk of premature birth, low weight at birth and other complications. Epigenetic changes caused by smoking can be transmitted from mother to child.

2.4. Alcohol: dual epigenetic sword

The use of alcohol has a complex effect on the epigenetic landscape. Moderate drinking of alcohol can have some positive effects, but excessive alcohol consumption has a negative effect on DNA methylation, modification of histones and the expression of small RNA, which increases the risk of cancer, liver diseases and other diseases.

• DNA methylation: Excessive alcohol consumption can lead to DNA hypomethylation and an increased risk of cancer.
• Modifications of histones: Excessive alcohol consumption can affect the modifications of histones, leading to changes in the structure of chromatin and genes expression.
• Expression of small RNA: Excessive alcohol consumption can affect the expression of small RNA, regulating inflammation and immune response.
• The risk of cancer development: Excessive alcohol use increases the risk of developing liver cancer, breast cancer, colon cancer and other types of cancer.
• Liver diseases: Excessive alcohol consumption can lead to the development of alcoholic liver disease, including fatty liver dystrophy, alcoholic hepatitis and cirrhosis of the liver.
• Pregnancy influence: The use of alcohol during pregnancy can have a negative effect on the development of the fetus, leading to fetal alcoholic syndrome, characterized by mental retardation, behavioral problems and physical defects.

2.5. Exposure toxins: epigenetic pollution

The impact of environmental toxins, such as heavy metals, pesticides and industrial chemicals, has a negative effect on the epigenetic landscape, causing changes in DNA methylation, modifications of histones and expression of small RNA, which increases the risk of cancer, neurodegenerative diseases and other diseases.

• Heavy metals: The influence of heavy metals, such as lead, mercury and cadmium, can cause changes in DNA methylization and modifications of histones, leading to the development of cancer and other diseases.
• Pesticides: The impact of pesticides can cause changes in DNA methylization and modifications of histones, leading to the development of cancer, neurodegenerative diseases and other diseases.
• Industrial chemicals: The impact of industrial chemicals, such as dioxins and polychlored biphenils (PHB), can cause changes in DNA methylization and modifications of histones, leading to the development of cancer and other diseases.
• Endocrine destroyers: Some toxins of the environment, such as bisphenol A (BFA) and fluids, are endocrine destroyers, that is, they can imitate or block the effect of hormones. The effect of endocrine destroyers can cause changes in DNA methylization and modifications of histones, leading to cancer, impaired reproductive function and other diseases.
• Impact of Development: The influence of environmental toxins during pregnancy can have a negative effect on the development of the fetus, leading to developmental defects, a decrease in cognitive abilities and increased risk of developing diseases in further life.

Chapter 3: Epigenetics and disease: from cancer to neurodegeneration

Epigenetic changes play an important role in the development of many diseases, including cancer, cardiovascular diseases, diabetes, neurodegenerative diseases and mental disorders.

3.1. Cancer: epigenetic aberration in cellular division

Cancer is often associated with aberrant epigenetic changes, which lead to a violation of the regulation of genes expression and uncontrolled cellular division.

• Hypermethylization of tumor-soup genes: Hypermethylization of promotional regions of tumor-sons, such as P16 and BRCA1, can lead to their inactivation and increased risk of cancer.
• Gipometilirovani Oncogenov: Hypomethylation of oncogenes, such as Myc and RAS, can lead to their increased expression and uncontrolled cellular division.
• Modifications of histones: Aberrant modifications of histones, such as a decrease in H3K9 acetylation and an increase in H3K27 methylation, are also associated with cancer development.
• Expression of small RNA: Mirna aberrant expression regulating proliferation, apoptosis and metastasis also plays a role in the development of cancer.
• Epigenetic therapy: Epigenetic therapy aimed at restoring normal epigenetic patterns is a promising direction in the treatment of cancer. Preparations, such as DNMTS inhibitors (azacitidine and decitabin) and HDACS inhibitors (thorinostate and romidepsin) are used to treat some types of blood cancer.

3.2. Cardiovascular diseases: epigenetic trace of atherosclerosis

Epigenetic changes play a role in the development of atherosclerosis, hypertension and other cardiovascular diseases.

• Atherosclerosis: Epigenetic changes affect the expression of genes involved in inflammation, lipid metabolism and proliferation of smooth muscle cells in the wall of arteries, which contributes to the development of atherosclerosis.
• Hypertension: Epigenetic changes affect the expression of genes that regulate blood pressure, such as the gene of endothelial syntase of nitrogen oxide (ENOS).
• Heart failure: Epigenetic changes affect the expression of genes involved in the contractility of the heart muscle and remodeling of the heart.
• The influence of the way of life: Life lifestyle factors, such as diet, smoking and physical activity, can affect epigenetic patterns in the cells of the cardiovascular system, which affects the risk of cardiovascular diseases.

3.3. Diabetes: epigenetic heritage of metabolic stress

Epigenetic changes play a role in the development of type 2 diabetes and its complications.

• Type 2 diabetes: Epigenetic changes affect the expression of genes involved in the secretion of insulin, sensitivity to insulin and glucose metabolism.
• Diabetes complications: Epigenetic changes affect the expression of genes involved in the development of complications of diabetes, such as nephropathy, retinopathy and neuropathy.
• Diet influence: The mother’s diet during pregnancy can affect the epigenetic patterns in her offspring, which affects the risk of type 2 diabetes.
• Epigenetic therapy: The possibility of using epigenetic therapy for the treatment of type 2 diabetes and its complications is investigated.

3.4. Neurodegenerative diseases: epigenetic failure in the brain

Epigenetic changes play a role in the development of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and other neurodegenerative diseases.

• Alzheimer’s disease: Epigenetic changes affect the expression of genes involved in the formation of amyloid plaques and neurofibrillar balls, which are Alzheimer Hallmarks.
• Parkinson’s disease: Epigenetic changes affect the expression of genes involved in the survival of dopaminergic neurons in the black substance of the brain.
• Huntington disease: Epigenetic changes affect the expression of the HuntingTin (HTT) gene, a mutation in which the Huntington disease causes.
• Environmental influence: The effect of environmental toxins, such as pesticides and heavy metals, can increase the risk of developing neurodegenerative diseases, partly due to epigenetic changes.

3.5. Mental disorders: epigenetic traces of injury and stress

Epigenetic changes play a role in the development of schizophrenia, depression, anxiety disorders and post -traumatic stress disorders (PTSD).

• Schizophrenia: Epigenetic changes affect the expression of genes involved in the development of the brain and neurotransmission.
• Depression: Epigenetic changes affect the expression of genes involved in the regulation of mood and a stress response.
• Alarm disorders: Epigenetic changes affect the expression of genes involved in the regulation of fear and anxiety.
• PTSR: Epigenetic changes affect the expression of genes involved in the formation and consolidation of memory of traumatic events.
• The influence of early experience: Early experience, such as cruel treatment and neglect, can cause epigenetic changes that increase the risk of developing mental disorders in further life.

Chapter 4: Epigenetics and Age: the effect of time on the genome

Epigenetic changes accumulate with age and play a role in aging and age-associated diseases.

4.1. Epigenetic watches: dimension of biological age

• DNA methylation: DNA methylation patterns change with age. Some CPG stations become hypermethylated, while others become hypometolic. These changes can be used to assess the biological age of the body.
• Horvath’s Clock: One of the most famous epigenetic watches, developed by Steve Croat, is based on the analysis of DNA methylation in 353 CPG-fasteners and can be used to assess the age of various tissues and organs.
• Other epigenetic hours: There are other epigenetic hours based on the analysis of DNA methylation, histones modifications and small RNA expression.
• Application of epigenetic watches: Epigenetic watches can be used to assess the risk of developing age-associated diseases, such as cancer, cardiovascular diseases and Alzheimer’s disease. They can also be used to assess the effectiveness of various aging strategies, such as diet and physical exercises.

4.2. The influence of epigenetic changes on aging

• DNA methylation: Age-related changes in DNA methylization can lead to a violation of the regulation of genes expression and cell dysfunction.
• Modifications of histones: Age -related changes in the modifications of histones can lead to changes in the structure of chromatin and the availability of DNA for transcription factors.
• Expression of small RNA: Age -related changes in the expression of small RNA can lead to a violation of the regulation of metabolism, inflammation and an immune response.
• Stem cell aging: Epigenetic changes can lead to a decrease in stem cell function, which contributes to the aging of tissues and organs.

4.3. The possibilities of epigenetic intervention in the aging process

• Diet and lifestyle: Diet and lifestyle can affect epigenetic patterns and slow down the aging process.
• Pharmacological interventions: The possibilities of using pharmacological preparations such as DNMTS inhibitors and HDACS inhibitors are investigated to slow down the aging process.
• Epigenetic editing: New technologies, such as CRISPR-CAS9, allow us to purposefully change epigenetic patterns and can be used to combat aging.

Chapter 5: Epigenetics and Future: therapeutic prospects and ethical issues

Epigenetics opens up new therapeutic opportunities for the treatment of various diseases and the prevention of aging. However, the development of epigenetic therapy raises important ethical issues.

5.1. Epigenetic therapy: new approaches to the treatment of diseases

• DNMTS inhibitors: DNMTS inhibitors (Azacitidine and decitabin) are used to treat some types of blood cancer, such as myelodisplay syndrome and acute myeloid leukemia.
• HDACS inhibitors: HDACS inhibitors (thorinostat and romidepsin) are used to treat some types of skin and lymphoma.
• MIRNA-therapy: Mirnut therapy aimed at modulating Mirna expression is a promising direction in the treatment of cancer, cardiovascular diseases and other diseases.
• Epigenetic editing: New technologies, such as CRISPR-CAS9, allow us to purposefully change epigenetic patterns and can be used to treat genetic and acquired diseases.

5.2. Epigenetic diagnostics: Early risk detection

• Biomarkers: Epigenetic changes, such as DNA methylation and expression of Mirna, can be used as biomarkers to early detect the risk of cancer, cardiovascular diseases and other diseases.
• Liquid biopsy: Liquid biopsy based on the analysis of DNA and RNA circulating in the blood can be used to monitor epigenetic changes in tumor cells and evaluate the effectiveness of cancer treatment.
• Personalized medicine: Epigenetic diagnostics can be used to develop personalized strategies for the prevention and treatment of diseases.

5.3. Ethical issues of epigenetics

• Impact of offspring: Epigenetic changes caused by lifestyle factors or therapeutic interventions can be transmitted to the following generations, which raises questions about responsibility for the consequences of these changes.
• Social inequality: Access to a healthy lifestyle and epigenetic therapy can be uneven, which can aggravate social inequality.
• Reductionism: Epigenetics should not be used to justify reductionist approaches to understanding health and diseases that ignore social and economic factors.
• Confidentiality: Information about epigenetic patterns can be used to discriminate in insurance and employment, which requires confidentiality.

Chapter 6: Practical recommendations: how to optimize your epigenetic landscape

Although epigenetics is a complex and rapidly developing area of ​​science, there are practical steps that everyone can take to optimize their epigenetic landscape and improve their health.

• Healthy nutrition: Observe a balanced diet rich in fruits, vegetables, whole grain products and healthy fats. Limit the consumption of processed products, sugar and saturated fats.
• Regular physical activity: Do regular physical activity of moderate intensity, such as walking, running, swimming or riding a bicycle.
• Refusal of smoking: Refuse smoking and avoid passive smoking.
• Moderate alcohol consumption: Limit the use of alcohol to moderate quantities (no more than one drink per day for women and no more than two drinks per day for men).
• Avoid the effects of toxins: Avoid the effects of environmental toxins, such as pesticides, heavy metals and pro