Molecular genetics of idiopathic pulmonary fibrosis

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

Probable Mechanisms of COVID-19 Pathogenesis

This review paper focuses on the search for innovative directions in the study of COVID­19 viral infection with the purpose of improving the methods of its treatment and vaccination. Thus far, comprehensive data have been obtained on the ability of nonretroviral RNA viruses, including those replicated in the cytoplasm, to integrate fragments of their genomes into the host DNA. This mechanism provided by the reverse  transcriptase and integrase of endogenous retroelements leads to the persistence of nonretroviral RNA viruses  through the expression of viral proteins by the host genome, which may serve as a prerequisite for the survival of such viruses. DNA integration events play a role in the development of both the immunological response and protective antiviral responses through the RNA interference system. These mechanisms may depend on the phylogenetically ancient fossils of nonretroviral RNA sequences in animal genomes. The discovery of SARS-CoV-2 fragments in COVID­19 recovered patients suggests that the pathogenesis of this disease may be associated with the integration of SARS-CoV-2 genome fragments in the human genome by means of proteins of endogenous retroviral elements. This assumption can be confirmed by the data about the development in older patients of predominantly severe forms of COVID­19 with “hyperactive” immune reactions, which normally weaken with ageing. This may be attributed to age­related abnormal activation of  retrocells, which contribute to reverse transcription and integration of exogenous viruses. This assumption is supported by the presence of coronavirus components in the nuclei of infected cells and the change in the expression of LINE­1 in the lung tissue cells of SARS patients. Due to the probable role of retrocells in the COVID­19 pathogenesis, LINE­1 reverse transcriptase inhibitors and targeted therapy using microRNAs may be offered as promising treatments for COVID­19

Вероятная роль ретроэлементов в развитии опухоли Вильмса при хромосомных синдромах

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.В обзорной статье приведены результаты анализа накопленных в литературе данных об ассоциации опухоли Вильмса с хромосомными синдромами и поиск возможных причин данного феномена. В 10 % всех случаев нефробластома представлена наследственным опухолевым синдромом вследствие герминальных мутаций в генах-супрессорах, главным образом в гене WT1, реже в WT2, WTX, CTNNB1, TP53. Данные гены характеризуются связью с ретроэлементами, которые играют важную роль в развитии опухоли Вильмса, способствуя канцерогенезу, вызывая геномную нестабильность. Ретроэлемент LINE-1 – негативный регулятор экспрессии WT1, в то время как гены-супрессоры подавляют активность ретроэлементов. Частью патогенеза синдромов Перлмана, Беквита–Видемана, WAGR, трисомии 18, обусловленных герминальными микроделециями, является активация ретроэлементов, способствующих соматическим хромосомным перестройкам, включая делеции, инсерции и транслокации, которые характерны для спорадической опухоли Вильмса. Кроме этого, ретроэлементы являются источниками длинных некодирующих РНК и микроРНК при процессинге их транскриптов или в эволюции генов. При этом длинные некодирующие РНК влияют на развитие опухоли Вильмса различными механизмами: за счет влияния на ферроптоз (lncRNA AC007406.1, AC005208.1, LINC01770, DLGAP1-AS2, AP002761.4, STPG3-AS1, AC129507.1, AC234772.2, LINC02447, AC009570.1, ZBTB20-AS1 и LINC01179), на сигнальные пути Wnt/β-катенина (HOTAIR, MEG3), апоптоз (HAGLROS), на регуляцию экспрессии специфических микроРНК (SNHG6, MEG8, XIST, SNHG16, DLEU1, CRNDE, SNHG6, DLGAP1, OSTM1-AS1, EMX2OS, H19).Анализ базы данных MDTE DB позволил обнаружить ассоциированные с нефробластомой микроРНК, которые происходят от ретротранспозонов. К ним относятся miR-192, -335, -378c, -562, -630, -1248. Эти молекулы перспективны в отношении возможного использования для патогенетического лечения опухоли Вильмса вследствие воздействия на патологически активированные ретротранспозоны. 

INTERRELATION OF PRIONS WITH NON-CODING RNAS

Prions are alternative infectious conformations for some cellular proteins. For the protein PrPC (PrP – prion protein, С – common), a prion conformation, called PrPSc (S – scrapie), is pathological. For example, in mammals the PrPSc prion causes transmissible spongiform encephalopathies accumulating in the brain tissues of PrPSc aggregates that have amyloid properties. MicroRNAs and long non-coding RNAs can be translated into functional peptides. These peptides can have a regulatory effect on genes from which their non-coding RNAs are transcribed. It has been assumed that prions, like peptides, due to the presence of specific domains, can also activate certain non-coding RNAs. Some of the activated non-coding RNAs can catalyze the formation of new prions from normal protein, playing their role in the pathogenesis of prion diseases. Confirmation of this assumption is the presence of the association of alleles of microRNA with the development of the disease, which indicates the role of the specific sequences of noncoding RNAs in the catalysis of prion formation. In the brain tissues of patients with prion diseases, as well as in exosomes containing an abnormal PrPSc isoform, changes in the levels of microRNA have been observed. A possible cause is the interaction of the spatial domains of PrPSc with the sequences of the non-coding RNA genes, which causes a change in their expression. MicroRNAs, in turn, affect the synthesis of long non-coding RNAs. We hypothesize that long noncoding RNAs and possibly microRNAs can interact with PrPC catalyzing its transformation into PrPSc. As a result, the number of PrPSc increases exponentially. In the brain of animals and humans, transposon activity has been observed, which has a regulatory effect on the differentiation of neuronal stem cells. Transposons form the basis of domain structures of long non-coding RNAs. In addition, they are important sources of microRNA. Since prion diseases can arise as sporadic and hereditary cases, and hereditary predisposition is important for the development of pathology, we hypothesize the role of individual features of activation of transposons in the pathogenesis of prion diseases. The activation of transposons in the brain at certain stages of development, as well as under the influence of stress, is reflected in the peculiarities of expression of specific non-coding RNAs that are capable of catalyzing the transition of the PrPC protein to PrPSc. Research in this direction can be the basis for targeted anti-microRNA therapy of prion diseases

Атипичные формы и гено-фенотипические корреляции нейрофиброматоза 1-го типа

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.Цель исследования – анализ данных об атипичных формах нейрофиброматоза 1-го типа и генофенотипических корреляциях при этом заболевании. Материал и методы. Поиск соответствующих источников проводился в системах Scopus, Web of Science, PubMed с включением публикаций с мая 1993 г. по октябрь 2021 г. Из 318 найденных исследований 59 были использованы для написания систематического обзора. Результаты. Найдены работы с описанием атипичных форм нейрофиброматоза 1-го типа со стертым течением без проявления опухолевого синдрома, которые обусловлены специфическими мутациями в гене NF1 (вызывающими замены аминокислот в нейрофибромине: p.Arg1038, p.Met1149, p.Arg1809, или делецию аминокислот: p.Met990del, p.Met992del). Для больных с микроделециями всего гена NF1 и прилегающих областей характерны более тяжелые проявления нейрофиброматоза 1-го типа (чаще проявляются лицевой дизморфизм, скелетные и сердечно-сосудистые аномалии, трудности в обучении и симптоматические спинальные нейрофибромы). С ранней манифестацией опухолей ассоциированы мутации сайтов сплайсинга и протяженные делеции гена NF1, с глиомами зрительных нервов – мутации на 5’-конце гена, вызывающие укорочение белкового продукта, со структурным поражением головного мозга – мутация c.3721C>T (p.R1241*), с эндокринными расстройствами – мутация c.6855C>A (p.Y2285*). Описана клиническая картина нейрофиброматоза 1-го типа, схожая с липоматозом и синдромом Джаффе–Кампаначчи, не связанная с конкретным типом мутации. Заключение. Несмотря на выраженную клиническую вариабельность нейрофиброматоза 1-го типа даже у членов одной семьи, в ряде работ описаны гено-фенотипические корреляции. Так как белок нейрофибромин имеет сложную структуру с несколькими функциональными доменами, предполагается роль генов-модификаторов и эпигенетических факторов в патогенезе нейрофиброматоза 1-го типа. Показано, что на выраженность опухолевого синдрома влияют особенности метилирования гена NF1 и прилегающих областей, а сам ген взаимосвязан с определенными микроРНК. Поэтому перспективным способом лечения нейрофиброматоза 1-го типа может стать таргетная терапия, нацеленная на специфические некодирующие РНК для восстановления нормальной экспрессии гена NF1

The role of transposable elements in the ecological morphogenesis under the influence of stress

In natural selection, insertional mutagenesis is an important source of genome variability. Transposons are sensors of environmental stress effects, which contribute to adaptation and speciation. These effects are due to changes in the mechanisms of morphogenesis, since transposons contain regulatory sequences that have cis and trans effects on specific protein-coding genes. In variability of genomes, the horizontal transfer of transposons plays an important role, because it contributes to changing the composition of transposons and the acquisition of new properties. Transposons are capable of site-specific transpositions, which lead to the activation of stress response genes. Transposons are sources of non-coding RNA, transcription factors binding sites and protein-coding genes due to domestication, exonization, and duplication. These genes contain nucleotide sequences that interact with non-coding RNAs processed from transposons transcripts, and therefore they are under the control of epigenetic regulatory networks involving transposons. Therefore, inherited features of the location and composition of transposons, along with a change in the phenotype, play an important role in the characteristics of responding to a variety of environmental stressors. This is the basis for the selection and survival of organisms with a specific composition and arrangement of transposons that contribute to adaptation under certain environmental conditions. In evolution, the capability to transpose into specific genome sites, regulate gene expression, and interact with transcription factors, along with the ability to respond to stressors, is the basis for rapid variability and speciation by altering the regulation of ontogenesis. The review presents evidence of tissue-specific and stage-specific features of transposon activation and their role in the regulation of cell differentiation to confirm their role in ecological morphogenesis

Involvement of transposable elements in neurogenesis

The article is about the role of transposons in the regulation of functioning of neuronal stem cells and mature neurons of the human brain. Starting from the first division of the zygote, embryonic development is governed by regular activations of transposable elements, which are necessary for the sequential regulation of the expression of genes specific for each cell type. These processes include differentiation of neuronal stem cells, which requires the finest tuning of expression of neuron genes in various regions of the brain. Therefore, in the hippocampus, the center of human neurogenesis, the highest transposon activity has been identified, which causes somatic mosai cism of cells during the formation of specific brain structures. Similar data were obtained in studies on experimental animals. Mobile genetic elements are the most important sources of long non-coding RNAs that are coexpressed with important brain protein-coding genes. Significant activity of long non-coding RNA was detected in the hippocampus, which confirms the role of transposons in the regulation of brain function. MicroRNAs, many of which arise from transposon transcripts, also play an important role in regulating the differentiation of neuronal stem cells. Therefore, transposons, through their own processed transcripts, take an active part in the epigenetic regulation of differentiation of neurons. The global regulatory role of transposons in the human brain is due to the emergence of protein-coding genes in evolution by their exonization, duplication and domestication. These genes are involved in an epigenetic regulatory network with the participation of transposons, since they contain nucleotide sequences complementary to miRNA and long non-coding RNA formed from transposons. In the memory formation, the role of the exchange of virus-like mRNA with the help of the Arc protein of endogenous retroviruses HERV between neurons has been revealed. A possible mechanism for the implementation of this mechanism may be reverse transcription of mRNA and site-specific insertion into the genome with a regulatory effect on the genes involved in the memory

Аваскулярный некроз головки бедренной кости в Республике Башкортостан (клинико-эпидемиологическое исследование)

Introduction. Avascular necrosis of the femoral head (AVNFH) is a relatively rare complex disease that occurs in people of working age and leads to disability due to irreversible changes in the aff ected hip joint. Aetiology of the disease has not been reliably established so far.Materials and methods. Among a total of 42,877 residents of Ufa surveyed, 71 were diagnosed with AVNFH. Patients granted an informed consent to conduct the survey, access the outpatient history of concomitant pathology, perform hip X-ray and laboratory blood tests.Results and discussion. Th e AVNFH incidence rate was 166 per 100,000 people, with the men to women ratio 1:1.5 and average age of manifestation 50 years. Secondary necrosis was established in 14, and bilateral lesion — in 42 % of cases. A family with hereditary AVNFH (mother, daughter and grandmother) was observed. A significantly higher incidence rate was observed with children in mononational families, which suggests a protective role of crossbreeding against this pathology. In 31 % of patients, the disease manifested atypically resembling lumbago with sciatica, which entailed a late AVNFH diagnosis. Smoking and long-term contact with chemicals were identified as the risk factors, and hypertension, chronic cerebral ischemia, anaemia, hypercholesterolemia and chronic inflammation — as associated disorders. A radiological profi le of the disease is described.Conclusion. Th e study allowed a precise estimation of the AVNFH incidence rate as 1 per 600 people. Idiopathic AVNFH occurred in 86 % of cases, with smoking and professional long-term contact with chemical agents as associated risk factors. Pedigree studies exposed a low incident rate in ethnically mixed families. AVNFH was shown comorbid with the hypertensive disease in 56 and chronic cerebral ischemia — in 42 % of patients. Atypical lumbago-sciatica-like symptoms in 1/3 of AVNFH cases warrant the need to conduct hip X-ray and MRI in this category of patients.Введение. Аваскулярный некроз головки бедренной кости (АНГБК) — относительно редкое заболевание со сложным патогенезом, поражающее людей трудоспособного возраста и приводящее к инвалидизации вследствие необратимых изменений в пораженном тазобедренном суставе. Достоверных данных об этиологии болезни до сих пор не получено.Материалы и методы. Исследовано 42 877 жителей города Уфы, среди которых выявлен 71 случай АНГБК. С согласия больных проведено их анкетирование, изучение амбулаторных карт с выявлением сопутствующей патологии, рентгенография тазобедренных суставов, лабораторные исследования крови.Результаты и обсуждение. Распространенность АНГБК составила 166 на 100 000, соотношение мужчин к женщинам — 1:1,5, средний возраст манифестации — 50 лет. Вторичный некроз выявлен в 14 %, двусторонне поражение — в 42 % случаев. Обнаружена семья с наследственной формой болезни (мама, дочь и бабушка). Определено значительное преобладание больных от родителей одной национальности, что позволяет предположить протективную роль метисации в отношении данной патологии. У 31 % пациентов болезнь характеризовалась атипичной клиникой, напоминающей люмбаго с ишиасом, в связи с чем АНГБК диагностировался на поздней стадии. Факторами риска болезни оказались курение и длительный контакт с химическими веществами, выявлена ассоциация с гипертонической болезнью, хронической ишемией головного мозга, анемией, гиперхолестеринемией и воспалительными процессами. Представлены данные выявленных особенностей рентгенологической картины заболевания.Заключение. Проведенное исследование позволило установить точную частоту встречаемости АНГБК — 1 случай на 600 человек. Идиопатический АНГБК составил 86 %, с влиянием на развитие болезни таких факторов риска, как курение и длительный контакт с химическими агентами на производстве. Анализ родословных больных показал низкий процент пациентов в смешанных по этнической принадлежности браках. Выявлена коморбидность АНГБК с гипертонической болезнью у 56 % пациентов и с хронической ишемией головного мозга (42 %). Атипичная клиника у 1/3 больных АНГБК с напоминающими люмбаго с ишиасом симптомами говорят о необходимости проведения рентгенографии и МРТ тазобедренных суставов у данной категории пациентов

Взаимосвязь транспозонов с длинными некодирующими РНК и пептидами в канцерогенезе

It has been proven that 98 % of the human genome is transcribed. The main part of resulting molecules after their processing function as various RNA molecules, among which the best known are long noncoding RNA (lncRNA)  and microRNA. There are 126,000 lncRNA genes in humans that regulate transcription, translation, histone modifications, heterochromatin formation, splicing, microRNA expression and formation, and matrix RNA (mRNA)  post-transcriptional modifications. An important property of lncRNAs is their mutual and self-regulation by peptides formed during their translation, which also affect the expression of protein-coding genes. This property may be due to origin of lncRNAs from transposable elements and is a conservative evolutionary characteristic of lncRNA, as one of properties in formation of new genes for variability and adaptation.  The role of lncRNAs originating from retroelements and microRNAs formed during their processing in the specific regulation of genes involved in carcinogenesis has been proven. The peptides formed during lncRNA translation can be used as universal tools for targeted therapy of malignant neoplasms. Analysis of the scientific literature  made it possible to describe 21 lncRNAs that  are translated  to form peptides involved in specific tumors pathogenesis. Since the ability of lncRNA to self-regulate by products of its own translation, which is characteristic of all lncRNAs, is also a property of transposable elements, it is promising to study transposons and their relationship with lncRNAs for designing new therapeutic models.Доказано, что 98 % генома человека транскрибируется. Основная часть образующихся при этом молекул после их процессинга функционирует в качестве различных молекул РНК, среди которых наиболее известны длинные некодирующие РНК (днРНК) и микроРНК. У человека выявлены 126 тыс. генов днРНК, регулирующих транскрипцию, трансляцию, модификации гистонов, образование гетерохроматина, сплайсинг, экспрессию и формирование микроРНК, а также посттранскрипционные модификации матричной РНК (мРНК). Важным свойством днРНК является взаимо- и саморегуляция образующимися при их трансляции пептидами, которые влияют также на экспрессию белок-кодирующих генов. Данное свойство может быть обусловлено происхождением днРНК от транспозонов и представляет собой консервативную эволюционную характеристику днРНК как одно из свойств при образовании новых генов для изменчивости и адаптации. Доказана роль возникших от ретроэлементов днРНК и образуемых при их процессинге микроРНК в специфической регуляции генов, участвующих в канцерогенезе. Образуемые при трансляции днРНК пептиды могут быть использованы как универсальные инструменты для таргетной терапии злокачественных новообразований. Анализ научной литературы позволил описать 21 днРНК, которая транслируется с образованием пептидов, вовлеченных в патогенез специфических опухолей. поскольку способность днРНК к саморегуляции продуктами собственной трансляции, которая характерна для всех днРНК, является также свойством транспозонов, перспективно исследование мобильных генетических элементов и их взаимосвязи с днРНК для проектирования новых терапевтических моделей