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The review article analyzes the data accumulated in the literature on the association of Wilms’ tumor with chromosomal syndromes and searches for possible causes of this phenomenon. In 10 % of all cases, nephroblastoma is represented by a hereditary tumor syndrome due to germline mutations in suppressor genes, mainly in the WT1 gene, less often in WT2, WTX, CTNNB1, TP53. These genes are associated with retroelements that play a role in the development of Wilms’ tumor, promoting carcinogenesis, causing genome instability. LINE-1 retroelement is a negative regulator of WT1 expression, while suppressor genes are characterized by suppression of retroelement activity. Part of the pathogenesis of Perlman, Beckwith-Wiedemann, WAGR, and trisomy 18 syndromes caused by germline microdeletions is the activation of retroelements that promote somatic chromosomal rearrangements, including deletions, insertions, and translocations, which are characteristic of sporadic Wilms’ tumor. Long noncoding RNAs and microRNAs are formed from retroelements during evolution or directly during the processing of their transcripts. At the same time, long noncoding RNAs affect the development of Wilms’ tumor by various mechanisms: due to the effect on ferroptosis (lncRNA AC007406.1, AC005208.1, LINC01770, DLGAP1-AS2, AP002761.4, STPG3-AS1, AC129507.1, AC234772.2, LINC02447, AC009570.1, ZBTB20-AS1 and LINC01179), Wnt/β-catenin signaling pathways (HOTAIR, MEG3), apoptosis (HAGLROS), regulation of expression of specific miRNAs (SNHG6, MEG8, XIST, SNHG16, DLEU1, CRNDE, SNHG6, DLGAP1, OSTM1-AS1, EMX2OS, H19). Analysis of the MDTE DB database revealed nephroblastoma-associated miRNAs that originate from retrotransposons. These include miR-192, -335, -378c, -562, -630, -1248. These molecules are promising for possible use in the pathogenetic treatment of Wilms’ tumor due to their effect on pathologically activated retrotransposons.

One of the mechanisms for the development of autoimmune diseases is changes in epigenetic regulation, the root causes of which have not yet been established. At the same time, data on the role of transposons as sources of long noncoding ribonucleic acids (RNA) and microRNAs involved in the development of immune pathology have been accumulated. In evolution, transposable elements have become the basis for the emergence of V(D)J recombination and regulation of HLA genes. Pathological transposon activation has been revealed in type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, AicardiGoutieres and Sjgrens syndromes. The influence of exogenous viruses on the development of autoimmune diseases may be due to their interactions with transposons. Transposable elements themselves are able to activate the antiviral immune response, stimulating the hyperproduction of interferon. An assumption about changes in the activation of transposons as drivers of autoimmune pathology was made, which is reflected in the expression of non-coding RNAs, which are key epigenetic factors. The analysis of the transposon-derived microRNA database (MDTE DB) made it possible to identify 13 microRNAs associated with autoimmune diseases: systemic scleroderma (miR-31, miR-609, miR-3162), juvenile rheumatoid arthritis (miR-151), systemic lupus erythematosus (miR-198, miR-342), psoriasis (miR-224, miR-378) and myasthenia gravis (miR-421, miR-551a, miR-612, miR-891b), multiple sclerosis (miR-584 ), which serves as a proof of the proposed hypothesis. Since changes in epigenetic factors under the influence of transposons are reversible and are reflected in the expression of certain non-coding RNAs, targeted therapy using microRNAs and their analogues as tools is a promising direction in the development of specific treatment for autoimmune diseases.

Frequency of atherosclerosis significantly increases with age, same as malignant tumor morbidity. Concurrent pathology (including in the cardiovascular system) affects selection of antitumor treatment limiting use of cardiotoxic (though highly effective) drugs. Statins are the main treatment for atherosclerosis but their study showed that regulation of cholesterol metabolism affects functioning of tumor cells. According to the results of clinical trial meta-analyses, regular use of statins decreases mortality in patients with bladder, prostate, renal, ovarian, lung, breast, and colorectal cancer both due to decreased risk of cardiovascular complications and increased effectiveness of antitumor drugs. In some studies, decreased risk of liver, esophageal, endometrial, renal, gastric, and pancreatic cancers was observed in patients taking statins. Antitumor effects of statins are supposedly mediated by decreased cholesterol production which is used by tumor cells for functioning and membrane synthesis. Additionally, statins inactivate RAS and RHO oncogenes by suppressing their isoprenylation, inhibit proliferation of tumor cells. Statins also contribute to activation of antitumor immunity, increased ferroptosis and autophagy. Statins activate apoptosis by interacting with mitochondrial procaspase 9, inhibit expression of toll-like receptors (TLR4), NF-κB, tumor necrosis factor α, interleukins 1β and 6, suppress the mTOR pathway. Therefore, multifaceted direct and indirect antitumor effects of statins show that these pharmaceuticals should be more intently considered as a component of antitumor therapy.

Neurofibromatosis type 1 is caused by a germline mutation in the NF1 gene encoding the tumor suppressor neurofibromin. Deficiency of this protein causes hyperactivation of Ras proto-oncogenes. This leads to the development of tumors. Ras proteins undergo prenylation, which is inhibited by inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase. Therefore, statins can be proposed as anticancer drugs in the complex treatment of neurofibromatosis type 1. Clinical studies have proven the effectiveness of statins in the treatment of sporadic malignant neoplasms, in the pathogenesis of which mutations in the NF1 gene play an important role. Various pathways of the influence of these drugs on the development of tumors are described, including the activation of autophagy, ferroptosis, suppression of proliferation, stimulation of antitumor immunity, and effects on the microenvironment of neoplasms. Data on the effect of statins on the development and progression of neurofibromas in patients with neurofibromatosis type 1 are not presented in the scientific literature. However, it was found that statins enhance the effect of anticancer drugs, the use of which in monotherapy against malignant neoplasms associated with neurofibromatosis is ineffective. In this regard, despite the inefficiency of statins in cognitive disorders in patients with neurofibromatosis type 1, the introduction of these drugs into clinical practice in combination with other drugs could provide a pleiotropic effect, affect various links in the pathogenesis of the disease.

Purpose of the study: Analysis of available data on geno-phenotypic correlations and atypical forms of neurofibromatosis type 1. Material and methods. We searched for relevant sources in the Scopus, Web of Science, PubMed systems, including publications from May 1993 to October 2021. Of the 318 studies we identified, 59 were used to write a systematic review. Results. We found studies describing atypical forms of neurofibromatosis type 1 with an erased course without manifestation of a tumor syndrome, which are caused by specific mutations in the NF1 gene (causing substitutions of amino acids in neurofibromin: p.Arg1038, p.Met1149, p.Arg1809, or deletion of amino acids: p.Met990del, p.Met992del). NF1 patients with microdeletions are characterized by more severe disease symptoms (more often facial dysmorphism, skeletal and cardiovascular abnormalities, learning difficulties, and symptomatic spinal neurofibromas). mutations of splicing sites and extended deletions of the NF1 gene are associated with early manifestation of tumors, mutations at the 5’-end of the gene, causing a shortening of the protein product, are associated with optic nerve gliomas. the mutation c.3721C>T (p.R1241*) correlated with structural brain damage, and c.6855C>A (p.Y2285*) with endocrine disorders. the manifestations of NF1, similar to lipomatosis and Jaffe-Campanacci syndrome, not associated with a specific type of mutation are described. Conclusion. In spite of pronounced clinical variability of the disease, even among members of the same family, several studies have described genotype-phenotype correlations. Therefore, the role of modifier genes and epigenetic factors in the pathogenesis of NF1 is assumed, since the neurofibromin protein has a complex structure with several functional domains. It has been shown that the severity of the tumor syndrome is influenced by the methylation characteristics of NF1 gene and adjacent areas. in addition, NF1 gene is associated with a variety of microRNAs. therefore, targeted therapy aimed at specific non-coding RNAs to restore normal expression of NF1 gene can become a promising treatment for NF1.

The risk of depression could be evaluated through its multifactorial nature using the polygenic score (PGS) approach. Assuming a “clinical continuum” hypothesis of mental diseases, a preliminary assessment of individuals with elevated risk for developing depression in a non-clinical group is of high relevance. In turn, epidemiological studies suggest including social/lifestyle factors together with PGS to address the “missing heritability” problem. We designed regression models, which included PGS using 27 SNPs and social/lifestyle factors to explain individual differences in depression levels in high-education students from the Volga–Ural region (VUR) of Eurasia. Since issues related to population stratification in PGS scores may lead to imprecise variant effect estimates, we aimed to examine a sensitivity of PGS calculated on summary statistics of depression and neuroticism GWAS from Western Europeans to assess individual proneness to depression levels in the examined sample of Eastern Europeans. A depression score was assessed using the revised version of the Beck Depression Inventory (BDI) in 1065 young adults (age 18–25 years, 79% women, Eastern European ancestry). The models based on weighted PGS demonstrated higher sensitivity to evaluate depression level in the full dataset, explaining up to 2.4% of the variance (p = 3.42 × 10−7); the addition of social parameters enhanced the strength of the model (adjusted r2 = 15%, p < 2.2 × 10−16). A higher effect was observed in models based on weighted PGS in the women group, explaining up to 3.9% (p = 6.03 × 10−9) of variance in depression level assuming a combined SNPs effect and 17% (p < 2.2 × 10−16)—with the addition of social factors in the model. We failed to estimate BDI-measured depression based on summary statistics from Western Europeans GWAS of clinical depression. Although regression models based on PGS from neuroticism (depression-related trait) GWAS in Europeans were associated with a depression level in our sample (adjusted r2 = 0.43%, p = 0.019—for unweighted model), the effect was mainly attributed to the inclusion of social/lifestyle factors as predictors in these models (adjusted r2 = 15%, p < 2.2 × 10−16—for unweighted model). In conclusion, constructed PGS models contribute to a proportion of interindividual variability in BDI-measured depression in high-education students, especially women, from the VUR of Eurasia. External factors, including the specificity of rearing in childhood, used as predictors, improve the predictive ability of these models. Implementation of ethnicity-specific effect estimates in such modeling is important for individual risk assessment.

Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome caused by a mutation in tumor suppressor gene NF1. The disease occurs with a frequency of 1:3000 of the population. Typical manifestations of NF1 are multiple cutaneous, subcutaneous and plexiform neurofibromas, which cause serious cosmetic defects in the appearance of patients. Since an effective method for the treatment of NF1 has not yet been introduced into clinical practice, which makes it possible to completely get rid of multiple neoplasms, surgical removal or the use of photodestruction methods remains the method of choice for the treatment of cutaneous and subcutaneous neurofibromas. However, plexiform neurofibromas infiltratively grow into the surrounding tissues, so their complete excision is often impossible. Therefore, surgical excision is indicated for localized forms of plexiform neurofibromas and in emergency situations when they are located near vital structures or in the presence of a mass effect. Moreover, excision of cutaneous and subcutaneous neurofibromas may initiate formation and growth of new tumors. This is due to the degranulation of mast cells in response to tumor damage, since the pathology of the immune system plays an important role in the development of neurofibromas. In order to avoid dissemination of tumors, it is also important to adhere to the principles of antiblastic surgery. Therefore, the most promising is the complex treatment of NF1 with the combined use of a classical approach, surgical laser, ketotifen, and an inhibitor of mitogen-activated kinase. This method can be recommended for the treatment of malignant peripheral nerve sheath tumors, as well as sporadic neoplasms, the resistance of which is caused by a somatic mutation in the NF1 gene. The goal of NF1 treatment is to improve the quality of life of the patient as a whole and reduce pain using an integrated multidisciplinary approach.

Recently, a lot of data has been gathered which demonstrates neurogenesis in the brain of adult humans. In genetics, findings have been obtained that not only prove, but also elucidate the molecular mechanisms of neurogenesis. In some publications, however, morphology disputes neuronal renewal in adulthood. Therefore, this review presents the modern achievements of epigenetics, morphology, and physiology, which confirm and characterize postnatal neurogenesis in detail. We suggest that the introduction of molecular genetic technologies into morphological studies will be the starting point for the integration of these areas, complementing each other for the introduction of targeted therapy in clinical practice. Numerous evidence has been obtained of the presence of postnatal neurogenesis in adult humans in studies using bromodeoxyuridine, a carbon isotope of 14C, and 3H-thymidine, in comparative analyses of experimental data from animals. Neuronal stem cells, represented by radial glia present in the subventricular and subgranular zones of the human brain, are morphologically similar to neuroepithelial cells. They express marker proteins for astrocytes, which suggests that the proliferation of neuroglia found in adults can also indicate the regeneration of neurons. To prove this, further studies are required, with the exact identification of newly-formed cells, using specific molecular markers, and data from modern epigenetics. The integration of molecular genetic methods into morphology will facilitate not only the accurate determination of the classification of cells to a specific subpopulation but also to study the effects of various agents on the proliferation of neurons in the adult brain.

Antitumor drug treatment of hemoblastoses always takes into account the patient comorbidity. Due to the frequent cardiovascular pathology and atherosclerosis, patients have to take statins along with antitumor treatment. Experimental studies have shown that statins inhibit the cholesterol synthesis (necessary for the vital activity of malignant cells), isoprenylation of the RAS and RHO oncogenes, and the proliferation of leukemic cells. In addition, the potentiation of antitumor drugs effect by statins, sensitization of leukemia and lymphomas cells to their effects were noted. when conducting a meta-analysis, it was found that mortality among patients with hematological malignancies taking statins is lower compared with the group of patients not receiving statins. This fact is probably explained not only by the improvement in cholesterol metabolism, but also by indirect antitumor effects of this group of drugs.

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome with a prevalence of 1:3000 in human population. About 50% of NF1 cases are sporadic due to newly emerging germline mutations in NF1 gene. Protein product of NF1 is a neurofibromin, which inhibits RAS-RAF-MEK-ERK system. The prevalence of NF1 is increasing as patients are fertile. Therefore, it is important to use rapid diagnostic methods for NF1 mutations in NF1 families for prenatal prophylaxis. Mutations in NF1 gene play roles in sporadic carcinogenesis and in development of cancer resistance to chemotherapy. Specific for NF1 are multiple subcutaneous and cutaneous neurofibromas, age spots, skeletal abnormalities, mental retardation, tumors of the brain and optic nerves. Half of patients with NF1 develop plexiform neurofibromas, which disfigure them or compress vital organs. The difficulty in treating NF1 is due to involvement of immune system, since a large number of degranulating mast cells are found in neurofibromas. Mast cells secrete cytokines that dont provide a proper anti-tumor immune response, but initiate formation and growth of new neurofibromas. Therefore, long-term administration of ketotiphen was proposed for treatment of NF1 patients. Surgical removal of neurofibromas causes relapses and induction of the growth of new tumors; therefore, it is necessary to develop an effective therapy for NF1. The effectiveness of complex therapy of NF1 with use of ketotiphen, Lydase and Aevit, as well as monotherapy with an ATP-independent inhibitor of mitogen-activated protein kinase, has been described. For widespread clinical implementation of these methods, it is necessary to conduct studies on large sample of patients, as well as to make medicines available for patients. Gene therapy may become promising in the treatment of NF1, which requires identification of the type of mutation in NF1 gene in each individual and the use of specific microRNAs.

The article presents a hypothesis about the influence of TP53 gene on the development of prostate, kidney, and bladder cancer through negative regulation of retrotransposons. The p53 protein is a transcription factor that controls the expression of various protein-coding genes. The promoter regions of endogenous retroviruses contain almost ideal binding sites for p53, which suppresses translation of these elements and LINE1s. The TP53 gene contains retrotransposons, which promote mutations due to recombinations. Germinal mutations of the TP53 gene in Li–Fraumeni syndrome cause a deficiency of the p53 protein, which leads to the activation of retroelements, which, in turn, cause loss of heterozygosity of the second TP53 allele. The result is a “vicious circle” that stimulates genomic instability and carcinogenesis. This mechanism is possible for sporadic urogenital system malignant neoplasms development, where TP53 mutations are most often identified, acting as drivers of carcinogenesis. At the same time, pathological activation of retroelements is found in many malignant neoplasms. Moreover, the “vicious circle”, when a deficiency of an oncosuppressor causes activation of retroelements that contribute to inactivation of other oncosuppressors, is characteristic not only for р53. Retroelements can be controlled by other oncosuppressor genes that contain hot spots of insertional mutagenesis and retrotransposons (which contribute to recombination events). I suppose that pathological interregulation of retroelements and tumor suppressors is a universal mechanism of carcinogenesis in the development of sporadic malignant neoplasms and hereditary tumor syndromes. Chromoplexy observed in 90 % of prostate cancer samples may reflect these events, since activated retroelements in carcinogenesis contribute to complex chromosomal rearrangements.

Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome occurring with a frequency of 1: 3000 of the population. NF1 is caused by germline heterozygous mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. The disease has a specific progressive course with multiple neurofibromas, in the initiation and growth of which NF1+/ – mast cells, macrophages and lymphocytes play an important role. Accordingly, the deficiency of neurofibromin impairs the differentiation and correct functioning of immune system cells. This is evidenced by the increased risk of leukemia in patients with NF1 and the role of NF1 mutations in the development of sporadic hematological malignancies. The development of neurofibromas is associated with the fact that NF1–/ – Schwann cells stimulate the migration of mast cells into the tumor microenvironment, which actively degranulate. The released cytokines promote neoangiogenesis, inflammation, fibroblast proliferation and the production of excess collagen. Therefore, in the treatment of NF1, the use of ketotifen and a kit/ fms kinase inhibitor is recommended. Macrophages and T-lymphocytes in neurofibromas do not provide an antitumor response, but promote inflammation and tumor growth. They produce STAT3 (signal transducer and activator of transcription 3), TGF-β, EGFR, IL-6, IL-4, and PD-1. Therefore, a promising direction is NF1 therapy with STAT3 inhibitors and immune checkpoint inhibitors that block programmed cell death ligand 1 (PD-L1). Activation of MEK signaling pathways in NF1 leads to PD-L1 stimulation; therefore, MEK inhibitors, which also suppress the RAS/RAF/MEK/ERK system, turned out to be effective in the treatment of NF1. For the treatment of sporadic malignant neoplasms, in the development of which NF1 mutations play a role, the developed methods of NF1 therapy can be used.

Cytochrome P450 is an enzyme involved in the metabolism of phase 1 xenobiotics, toxins, endogenous hormones, and drugs, including those used in COVID-19 treatment. Cytochrome p450 genes are linked to the pathogenesis of some multifactorial traits and diseases, such as cancer, particularly prostate cancer, colorectal cancer, breast cancer, and cervical cancer. Genotyping was performed on 540 supposedly healthy individuals of 5 Finno-Permic populations from the territories of the European part of the Russian Federation. There was a statistically significant difference between Veps and most of the studied populations in the rs4986774 locus of the CYP2D6 gene; data on the rs3892097 locus of the CYP2D6 gene shows that Izhemsky Komis are different from the Mordovian and Udmurt populations.

Retroelements play a key role in brain functioning in humans and other animals, since they represent dynamic regulatory elements controlling the expression of specific neuron types. The activity of retroelements in the brain is impaired under the influence of SARS-CoV-2, penetrating the blood-brain barrier. We propose a new concept, according to which the neurological complications of COVID-19 and their long-term effects are caused by modified expression of retroelements in neurons due to viral effect. This effect is implemented in several ways: a direct effect of the virus on the promoter regions of retroelement-encoding genes, virus interaction with miRNAs causing silencing of transposons, and an effect of the viral RNA on the products of retroelement transcription. Aging-related physiological activation of retroelements in the elderly is responsible for more severe course of COVID-19. The associations of multiple sclerosis, Parkinson’s disease, Guillain-Barré syndrome, acute disseminated encephalomyelitis with coronavirus lesions also indicate the role of retroelements in such complications, because retroelements are involved in the mechanisms of the development of these diseases. According to meta-analyses, COVID-19-caused neurological complications ranged 36.4-73%. The neuropsychiatric consequences of COVID-19 are observed in patients over a long period after recovery, and their prevalence may exceed those during the acute phase of the disease. Even 12 months after recovery, unmotivated fatigue, headache, mental disorders, and neurocognitive impairment were observed in 82%, 60%, 26.2-45%, and 16.2-46.8% of patients, correspondingly. These manifestations are explained by the role of retroelements in the integration of SARS-CoV-2 into the human genome using their reverse transcriptase and endonuclease, which results in a long-term viral persistence. The research on the role of specific retroelements in these changes can become the basis for developing targeted therapy for neurological consequences of COVID-19 using miRNAs, since epigenetic changes in the functioning of the genome in neurons, affected by transposons, are reversible.

To date, multiple efforts have been made to use genome-wide association studies (GWAS) to untangle the genetic basis for SARS-CoV-2 infection susceptibility and severe COVID-19. However, data on the genetic-related effects of SARS-CoV-2 infection on the presence of accompanying and long-term post-COVID-19 neurological symptoms in younger individuals remain absent. We aimed to examine the possible association between SNPs found in a GWAS of COVID-19 outcomes and three phenotypes: SARS-CoV-2 infection, neurological complications during disease progression, and long-term neurological complications in young adults with a mild-to-moderate disease course. University students (N = 336, age 18–25 years, European ancestry) with or without COVID-19 and neurological symptoms in anamnesis comprised the study sample. Logistic regression was performed with COVID-19-related phenotypes as outcomes, and the top 25 SNPs from GWAS meta-analyses and an MR study linking COVID-19 and cognitive deficits were found. We replicated previously reported associations of the FURIN and SLC6A20 gene variants (OR = 2.36, 95% CI 1.31–4.24) and OR = 1.94, 95% CI 1.08–3.49, respectively) and remaining neurological complications (OR = 2.12, 95% CI 1.10–4.35 for SLC6A20), while NR1H2 (OR = 2.99, 95% CI 1.39–6.69) and TMPRSS2 (OR = 2.03, 95% CI 1.19–3.50) SNPs were associated with neurological symptoms accompanying COVID-19. Our findings indicate that genetic variants related to a severe COVID-19 course in adults may contribute to the occurrence of neurological repercussions in individuals at a young age.

Idiopathic pulmonary fibrosis (IPF) is a severe progressive interstitial lung disease with a prevalence of 2 to 29 per 100,000 of the world's population. Aging is a significant risk factor for IPF, and the mechanisms of aging (telomere depletion, genomic instability, mitochondrial dysfunction, loss of proteostasis) are involved in the pathogenesis of IPF. The pathogenesis of IPF consists of TGF-β activation, epithelial-mesenchymal transition, and SIRT7 expression decrease. Genetic studies have shown a role of mutations and polymorphisms in mucin genes (MUC5B), in the genes responsible for the integrity of telomeres (TERC, TERC, TINF2, DKC1, RTEL1, PARN), in surfactant-related genes (SFTPC, SFTPCA, SFTPA2, ABCA3, SP-A2), immune system genes (IL1RN, TOLLIP), and haplotypes of HLA genes (DRB1*15:01, DQB1*06:02) in IPF pathogenesis. The investigation of the influence of reversible epigenetic factors on the development of the disease, which can be corrected by targeted therapy, shows promise. Among them, an association of a number of specific microRNAs and long noncoding RNAs was revealed with IPF. Therefore, dysregulation of transposons, which serve as key sources of noncoding RNA and affect mechanisms of aging, may serve as a driver for IPF development. This is due to the fact that pathological activation of transposons leads to violation of the regulation of genes, in the epigenetic control of which microRNA originating from these transposons are involved (due to the complementarity of nucleotide sequences). Analysis of the MDTE database (miRNAs derived from Transposable Elements) allowed the detection of 12 different miRNAs derived in evolution from transposons and associated with IPF (miR-31, miR-302, miR-326, miR-335, miR-340, miR-374, miR-487, miR-493, miR-495, miR-630, miR-708, miR-1343). We described the relationship of transposons with TGF-β, sirtuins and telomeres, dysfunction of which is involved in the pathogenesis of IPF. New data on IPF epigenetic mechanisms can become the basis for improving results of targeted therapy of the disease using noncoding RNAs.Идиопатический легочный фиброз – тяжелая прогрессирующая интерстициальная болезнь легких с распространенностью 2–29 случаев на 100 000 человек населения в мире. Значимым фактором риска заболевания является старение, механизмы развития которого задействованы в патогенезе идиопатического легочного фиброза. К ним относятся истощение теломер, геномная нестабильность, дисфункция митохондрий и потеря протеостаза. Важную роль в развитии идиопатического легочного фиброза играют также эпителиально-мезенхимальный переход, активация TGF-β и снижение экспрессии сиртуина SIRT7. Молекулярно-генетические исследования показали, что в патогенезе идиопатического легочного фиброза имеют значение мутации и полиморфизмы в генах муцина (MUC5B), в генах, ответственных за целостность теломер (TERC, TERT, TINF2, DKC1, RTEL1, PARN), генов сурфактанта (SFTPC, SFTPCA, SFTPA2, ABCA3, SP-A2) и иммунной системы (IL1RN, TOLLIP), а также гаплотипы генов HLA (DRB1*15:01, DQB1*06:02). Перспективно изучение влияния на развитие болезни обратимых эпигенетических факторов, которые могут быть скорректированы таргетной терапией. Среди них с идиопатическим легочным фиброзом ассоциированы специфические микроРНК и длинные некодирующие РНК. Сделано предположение, что драйверным событием для идиопатического легочного фиброза служит дисрегуляция транспозонов, которые являются ключевыми источниками некодирующих РНК и влияют на механизмы старения. Это обусловлено тем, что при патологической активации транспозонов происходит нарушение регуляции генов, в эпигенетическом управлении которых участвуют происходящие от этих транспозонов микроРНК (в связи с комплементарностью нуклеотидных последовательностей). Анализ базы данных MDTE (miRNAs derived from Transposable Elements) позволил выявить 12 различных микроРНК, гены которых в эволюции возникли от транспозонов и ассоциированы с идиопатическим легочным фиброзом (miR-31, miR-302, miR-326, miR-335, miR-340, miR-374, miR-487, miR-493, miR-495, miR-630, miR-708, miR-1343). Описаны взаимосвязи мобильных элементов с TGF-β, сиртуинами и теломерами, дисфункция которых вовлечена в патогенез идиопатического легочного фиброза. Новые данные об эпигенетических механизмах развития патологии могут стать основой для улучшения результатов таргетной терапии болезни с использованием в качестве мишени некодирующих РНК.

The key factor of genome instability during aging is transposon dysregulation. This may be due to senile changes in the expression of lamins, which epigenetically modulate transposons. Lamins directly physically interact with transposons. Epigenetic regulators such as SIRT7, BAF, and microRNA can also serve as intermediaries for their interactions. There is also an inverse regulation, since transposons are sources of miRNAs that affect lamins. We suggest that lamins can be attributed to epigenetic factors, since they are part of the NURD, interact with histone deacetylases and regulate gene expression without changing the nucleotide sequences. The role of lamins in the etiopathogenesis of premature aging syndromes may be associated with interactions with transposons. In various human cells, LINE1 is present in the heterochromatin domains of the genome associated with lamins, while SIRT7 facilitates the interaction of this retroelement with lamins. Both retroelements and the nuclear lamina play an important role in the antiviral response of organisms. This may be due to the role of lamins in protection from both viruses and transposons, since viruses and transposons are evolutionarily related. Transposable elements and lamins are secondary messengers of environmental stressors that can serve as triggers for aging and carcinogenesis. Transposons play a role in the development of cancer, while the microRNAs derived from them, participating in the etiopathogenesis of tumors, are important in human aging. Lamins have similar properties, since lamins are dysregulated in cancer, and microRNAs affecting them are involved in carcinogenesis. Changes in the expression of specif ic microRNAs were also revealed in laminopathies. Identif ication of the epigenetic mechanisms of interaction of lamins with transposons during aging can become the basis for the development of methods of life extension and targeted therapy of age-associated cancer.Дисбаланс активации транспозонов – один из важнейших факторов нестабильности генома при старении. Причинами этого явления могут быть ассоциированные с возрастом изменения экспрессии ламинов, которые влияют на эпигенетическую регуляцию мобильных генетических элементов. Взаимосвязь ламинов и транспозонов может быть обусловлена специфическим физическим контактом между молекулами, а также опосредована эпигенетическими регуляторами, такими как SIRT7, BAF и микроРНК. Характерна взаиморегуляция ламинов с мобильными элементами, которые являются источниками микроРНК, влияющими на ламины. Ламины входят в состав NURD (nucleosome remoldeling deacetylase complex), взаимодействуют с гистоновыми деацетилазами и регулируют экспрессию генов без изменения структуры нуклеотидных последовательностей. Роль ядерной ламины в этиопатогенезе синдромов преждевременного старения может быть обусловлена взаимодействием с транспозонами, так как истощение ламинов приводит к активации мобильных генетических элементов. В различных клетках человека LINE1 представлены в связанных с ламинами гетерохроматиновых доменах генома, при этом SIRT7 способствует взаимодействию данного ретроэлемента с ядерной ламиной. В противовирусном ответе организмов важную роль играют как ретроэлементы, так и ядерная ламина. Это согласуется с ролью ламинов в защите как от вирусов, так и от транспозонов, которые характеризуются филогенетическим родством. Мобильные генетические элементы и ламины – вторичные мессенджеры средовых стрессорных воздействий, которые могут служить пусковыми факторами для старения и канцерогенеза. Транспозоны играют роль в развитии злокачественных новообразований, при этом происходящие от них микроРНК, участвующие в этиопатогенезе опухолей, имеют значение в старении человека. Сходные свойства типичны для ламинов, поскольку при злокачественных новообразованиях выявлена дисрегуляция ламинов, а влияющие на них микроРНК участвуют в канцерогенезе. Изменение экспрессии специфических микроРНК отмечено также при ламинопатиях. Определение точных эпигенетических механизмов взаимодействия ламинов с мобильными генетическими элементами при старении может стать основой для разработки методов продления жизни и таргетной терапии ассоциированных с возрастом злокачественных новообразований.