Transposon Activation Research Articles

Correlation Between Subgenome-biased DNA Loss and DNA Transposon Activation Following Hybridization in the Allotetraploid Xenopus Frogs

Abstract In certain tetraploid species resulting from interspecific hybridization, one parent's subgenome is known to selectively undergo DNA loss. The molecular mechanisms behind this remain unclear. In our study, we compared the genomes of a standard diploid species with two allotetraploid species from the Xenopus genus, both possessing L (longer) and S (shorter) homoeologous subgenomes. We observed substantial gene losses and intergenic DNA deletions in both the S and L subgenomes of the tetraploid species. Gene losses were around 1,000 to 3,000 for L and 4,000 to 6,000 for S, with especially prominent losses in the S subgenome. Many of these losses likely occurred shortly after interspecific hybridization in both L/S subgenomes. We also deduced frequent large inversions in the S subgenome. Upon reassessing transposon dynamics using updated genome databases, we reaffirmed heightened DNA transposon activity during the hybridization, as previously reported. We next investigated whether S subgenome-biased DNA loss could be correlated with the activation of DNA transposons following hybridization. Notably, distinct patterns were observed in the dynamics of DNA transposons between the L and S subgenomes. Several DNA transposon subfamilies correlated positively with DNA deletions in the S subgenome and negatively in the L subgenome. Based on these results, we propose a model that, upon and after hybridization between two related diploid Xenopus species, the mixture of their genomes resulted in the derepression of DNA transposons, especially in the S subgenome, leading to selective DNA loss in the S subgenome.

A hypothesis about interrelations of epigenetic factors and transposable elements in memory formation.

The review describes the hypothesis that the drivers of epigenetic regulation in memory formation are transposable elements that influence the expression of specific genes in the brain. The hypothesis is confirmed by research into transposon activation in neuronal stem cells during neuronal differentiation. These changes occur in the hippocampus dentate gyrus, where a pronounced activity of transposons and their insertion near neuron-specific genes have been detected. In experiments on changing the activity of histone acetyltransferase and inhibition of DNA methyltransferase and reverse transcriptase, the involvement of epigenetic factors and retroelements in the mechanisms of memory formation has been shown. Also, a number of studies on different animals have revealed the preservation of long-term memory without the participation of synaptic plasticity. The data obtained suggest that transposons, which are genome sensors highly sensitive to various environmental and internal influences, form memory at the nuclear coding level. Therefore, long-term memory is preserved after elimination of synaptic connections. This is confirmed by the fact that the proteins involved in memory formation, including the transfer of genetic information through synapses between neurons (Arc protein), originate from transposons. Long non-coding RNAs and microRNAs also originate from transposons; their role in memory consolidation has been described. Pathological activation of transposable elements is a likely cause of neurodegenerative diseases with memory impairment. Analysis of the scientific literature allowed us to identify changes in the expression of 40 microRNAs derived from transposons in Alzheimer's disease. For 24 of these microRNAs, the mechanisms of regulation of genes involved in the functioning of the brain have been described. It has been suggested that the microRNAs we identified could become potential tools for regulating transposon activity in the brain in order to improve memory.

Epigenomic landscapes during prefrontal cortex development and aging in rhesus.

The prefrontal cortex (PFC) is essential for higher-level cognitive functions. How epigenetic dynamics participates in PFC development and aging is largely unknown. Here, we profiled epigenomic landscapes of rhesus monkey PFCs from prenatal to aging stages. The dynamics of chromatin states, including higher-order chromatin structure, chromatin interaction and histone modifications are coordinated to regulate stage-specific gene transcription, participating in distinct processes of neurodevelopment. Dramatic changes of epigenetic signals occur around the birth stage. Notably, genes involved in neuronal cell differentiation and layer specification are pre-configured by bivalent promoters. We identified a cis-regulatory module and the transcription factors (TFs) associated with basal radial glia development, which was associated with large brain size in primates. These TFs include GLI3, CREB5 and SOX9. Interestingly, the genes associated with the basal radial glia (bRG)-associated cis-element module, such as SRY and SOX9, are enriched in sex differentiation. Schizophrenia-associated single nucleotide polymorphisms are more enriched in super enhancers (SEs) than typical enhancers, suggesting that SEs play an important role in neural network wiring. A cis-regulatory element of DBN1 is identified, which is critical for neuronal cell proliferation and synaptic neuron differentiation. Notably, the loss of distal chromatin interaction and H3K27me3 signal are hallmarks of PFC aging, which are associated with abnormal expression of aging-related genes and transposon activation, respectively. Collectively, our findings shed light on epigenetic mechanisms underlying primate brain development and aging.

Epigenetic control over the cell-intrinsic immune response antagonizes self-renewal in acute myeloid leukemia

AbstractEpigenetic modulation of the cell-intrinsic immune response holds promise as a therapeutic approach for leukemia. However, current strategies designed for transcriptional activation of endogenous transposons and subsequent interferon type-I (IFN-I) response, show limited clinical efficacy. Histone lysine methylation is an epigenetic signature in IFN-I response associated with suppression of IFN-I and IFN-stimulated genes, suggesting histone demethylation as key mechanism of reactivation. In this study, we unveil the histone demethylase PHF8 as a direct initiator and regulator of cell-intrinsic immune response in acute myeloid leukemia (AML). Site-specific phosphorylation of PHF8 orchestrates epigenetic changes that upregulate cytosolic RNA sensors, particularly the TRIM25-RIG-I-IFIT5 axis, thereby triggering the cellular IFN-I response-differentiation-apoptosis network. This signaling cascade largely counteracts differentiation block and growth of human AML cells across various disease subtypes in vitro and in vivo. Through proteome analysis of over 200 primary AML bone marrow samples, we identify a distinct PHF8/IFN-I signature in half of the patient population, without significant associations with known clinically or genetically defined AML subgroups. This profile was absent in healthy CD34+ hematopoietic progenitor cells, suggesting therapeutic applicability in a large fraction of patients with AML. Pharmacological support of PHF8 phosphorylation significantly impairs the growth in samples from patients with primary AML. These findings provide novel opportunities for harnessing the cell-intrinsic immune response in the development of immunotherapeutic strategies against AML.

Relationship of MicroRNAs with Transposable Elements in the Type 1 Diabetes Development

The review article describes the involvement of epigenetic factors in type 1 diabetes mellitus (T1DM) etiopathogenesis. The disease is characterized by changes in expression of microRNAs that affect the transcription of genes involved in autoimmune reactions, destruction of beta cells and insulin production. However, the cause of the observed epigenetic changes is still unclear. In evolution, the sources of microRNA genes are transposable elements, which occupy up to 45 % of the entire human DNA sequence and are drivers of epigenetic regulation in ontogenesis. They are sources of transcription factor sequences and binding sites for them. Features of the genome distribution of transposable elements can cause changes in the number of 5’VNTR (variable number of tandem repeats) — repeats of insulin promoter region and HERV insertions into HLA genes, which affects their expression. Therefore, I assume that the cause of the development of type 1 diabetes mellitus may be an imbalance in transcription activation of transposons, which contributes to changes in the expression of specific microRNAs and protein-coding genes, and also contributes to autoimmune response development. Triggers for this may be individual features of genome distribution of transposons, viral infections and stress. An analysis of the scientific literature confirms my proposed mechanisms for T1DM development, since the global role of retroelements in hormonal regulation, the sensitivity of transposable elements to exogenous viral infections and stress, and HERV-W expression of the majority of patients with T1DM with activation of the autoimmune response have been proven. Analysis of the MDTE DB (miRNAs derived from transposable elements database) database showed the transposon origin of 12 T1DM-associated microRNAs (miR-192, miR-224, miR-31, miR-320c, miR-326, miR-340, miR-342, miR-44661, miR-548c, miR-652, miR-95), the use of which can become the basis for targeted therapy for T1DM.

Exploring the Effect of High-Energy Heavy Ion Beam on Rice Genome: Transposon Activation.

High-energy heavy ion beams are a new type of physical mutagen that can produce a wide range of phenotypic variations. In order to understand the mechanism of high-energy heavy ion beams, we resequenced the whole genome of individual plants with obvious phenotypic variations in rice. The sequence alignment results revealed a large number of SNPs and InDels, as well as genetic variations related to grain type and heading date. The distribution of SNP and InDel on chromosomes is random, but they often occur in the up/downstream regions and the intergenic region. Mutagenesis can cause changes in transposons such as Dasheng, mPing, Osr13 and RIRE2, affecting the stability of the genome. This study obtained the major gene mutation types, discovered differentially active transposons, screened out gene variants related to phenotype, and explored the mechanism of high-energy heavy ion beam radiation on rice genes.

Abstract 1116: Identifying neuroendocrine prostate cancer drivers using in vivo forward genetics

Abstract Prostate cancer (PC) is the malignancy with the highest incidence worldwide in males. Although localized disease can be effectively treated and usually has a favorable prognosis, progression to metastasis results in high mortality rates as current treatment modalities are not yet curative. The standard of care for advanced PC is hormonal therapy, termed Androgen Deprivation Therapy (ADT). Unfortunately, ADT typically elicits the emergence of a lethal phenotype, termed Castration-Resistant Prostate Cancer (CRPC), which is treatment-resistant and frequently gives rise to a highly aggressive variant with features of neuroendocrine (NE) differentiation, known as Neuroendocrine PC (NEPC). There is no cure for NEPC, thus identifying drivers that lead to its emergence is of paramount importance. We used the Sleeping Beauty (SB) transposon system to perform a forward genetic screening on Genetically-Engineered Mouse Models (GEMMs) of CRPC that are known to develop NEPC under ADT pressure. SB transposon activation generated tumors with an accelerated growth phenotype and increased metastasis incidence compared to non-activated controls. Notably, several tumors presented histological features of NEPC. We sequenced SB transposon integration sites on tumors’ genomes to identify recurrent patterns suggesting genes responsible for phenotype acceleration and NEPC differentiation. Recently, we generated and assembled a set of >100 GEMM-derived tumors, that recapitulate a broad spectrum of PC disease states, to reverse-engineer a network of regulatory proteins. We used this network on RNA-Seq data collected from SB-activated tumors to identify Master Regulator (MR) proteins that are specifically associated with NEPC emergence. Cross-species network analysis of patient-specific MRs activity conservation between patient and our mouse cohorts, aligned NEPC patients to mice tumors with NE features, corroborating our study's clinical relevance. We performed an integrative network analysis that links genomic events as generated by SB transposon integrations to downstream regulatory programs implemented by MR proteins. This analysis prioritized Sirt1 as upstream modulator of NEPC MRs activity. Activation of SIRT1 in human adenocarcinoma PC cells induced NE-like phenotype, while SIRT1 inhibitor in NEPC cells reduced tumor aggressiveness. In summary, we used in vivo models of prostate cancer to elucidate molecular drivers of NEPC, a lethal variant that is treatment-resistant. Integrative network data analysis prioritized Sirt1 as driver of NEPC emergence and was validated in vivo. Citation Format: Alessandro Vasciaveo, Francisca Nunes De Almeida, Min Zou, Matteo Di Bernardo, Andrea Califano, Cory Abate-Shen. Identifying neuroendocrine prostate cancer drivers using in vivo forward genetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1116.

Dynamics of histone acetylation during human early embryogenesis

It remains poorly understood about the regulation of gene and transposon transcription during human early embryogenesis. Here, we report that broad H3K27ac domains are genome-widely distributed in human 2-cell and 4-cell embryos and transit into typical peaks in the 8-cell embryos. The broad H3K27ac domains in early embryos before zygotic genome activation (ZGA) are also observed in mouse. It suggests that broad H3K27ac domains play conserved functions before ZGA in mammals. Intriguingly, a large portion of broad H3K27ac domains overlap with broad H3K4me3 domains. Further investigation reveals that histone deacetylases are required for the removal or transition of broad H3K27ac domains and ZGA. After ZGA, the number of typical H3K27ac peaks is dynamic, which is associated with the stage-specific gene expression. Furthermore, P300 is important for the establishment of H3K27ac peaks and the expression of associated genes in early embryos after ZGA. Our data also indicate that H3K27ac marks active transposons in early embryos. Interestingly, H3K27ac and H3K18ac signals rather than H3K9ac signals are enriched at ERVK elements in mouse embryos after ZGA. It suggests that different types of histone acetylations exert distinct roles in the activation of transposons. In summary, H3K27ac modification undergoes extensive reprogramming during early embryo development in mammals, which is associated with the expression of genes and transposons.

Hexavalent chromium-induced epigenetic instability and transposon activation lead to phenotypic variations and tumors in Drosophila.

Developmental robustness represents the ability of an organism to resist phenotypic variations despite environmental insults and inherent genetic variations. Derailment of developmental robustness leads to phenotypic variations that can get fixed in a population for many generations. Environmental pollution is a significant worldwide problem with detrimental consequences of human development. Understanding the genetic basis for how pollutants affect human development is critical for developing interventional therapies. Here, we report that environmental stress induced by hexavalent chromium, Cr(VI), a potent industrial pollutant, compromises developmental robustness, leading to phenotypic variations in the progeny. These phenotypic variations arise due to epigenetic instability and transposon activation in the somatic tissues of the progeny rather than novel genetic mutations and can be reduced by increasing the dosage of Piwi - a Piwi-interacting RNA-binding protein, in the ovary of the exposed mother. Significantly, the derailment of developmental robustness by Cr(VI) exposure leads to tumors in the progeny, and the predisposition to develop tumors is fixed in the population for at least three generations. Thus, we show for the first time that environmental pollution can derail developmental robustness and predispose the progeny of the exposed population to develop phenotypic variations and tumors.

Epigenetic Stress and Long-Read cDNA Sequencing of Sunflower (Helianthus annuus L.) Revealed the Origin of the Plant Retrotranscriptome.

Transposable elements (TEs) contribute not only to genome diversity but also to transcriptome diversity in plants. To unravel the sources of LTR retrotransposon (RTE) transcripts in sunflower, we exploited a recently developed transposon activation method ('TEgenesis') along with long-read cDNA Nanopore sequencing. This approach allows for the identification of 56 RTE transcripts from different genomic loci including full-length and non-autonomous RTEs. Using the mobilome analysis, we provided a new set of expressed and transpositional active sunflower RTEs for future studies. Among them, a Ty3/Gypsy RTE called SUNTY3 exhibited ongoing transposition activity, as detected by eccDNA analysis. We showed that the sunflower genome contains a diverse set of non-autonomous RTEs encoding a single RTE protein, including the previously described TR-GAG (terminal repeat with the GAG domain) as well as new categories, TR-RT-RH, TR-RH, and TR-INT-RT. Our results demonstrate that 40% of the loci for RTE-related transcripts (nonLTR-RTEs) lack their LTR sequences and resemble conventional eucaryotic genes encoding RTE-related proteins with unknown functions. It was evident based on phylogenetic analysis that three nonLTR-RTEs encode GAG (HadGAG1-3) fused to a host protein. These HadGAG proteins have homologs found in other plant species, potentially indicating GAG domestication. Ultimately, we found that the sunflower retrotranscriptome originated from the transcription of active RTEs, non-autonomous RTEs, and gene-like RTE transcripts, including those encoding domesticated proteins.

Transposons Acting as Competitive Endogenous RNAs: In-Silico Evidence from Datasets Characterised by L1 Overexpression.

LINE L1 are transposable elements that can replicate within the genome by passing through RNA intermediates. The vast majority of these element copies in the human genome are inactive and just between 100 and 150 copies are still able to mobilize. During evolution, they could have been positively selected for beneficial cellular functions. Nonetheless, L1 deregulation can be detrimental to the cell, causing diseases such as cancer. The activity of miRNAs represents a fundamental mechanism for controlling transcript levels in somatic cells. These are a class of small non-coding RNAs that cause degradation or translational inhibition of their target transcripts. Beyond this, competitive endogenous RNAs (ceRNAs), mostly made by circular and non-coding RNAs, have been seen to compete for the binding of the same set of miRNAs targeting protein coding genes. In this study, we have investigated whether autonomously transcribed L1s may act as ceRNAs by analyzing public dataset in-silico. We observed that genes sharing miRNA target sites with L1 have a tendency to be upregulated when L1 are overexpressed, suggesting the possibility that L1 might act as ceRNAs. This finding will help in the interpretation of transcriptomic responses in contexts characterized by the specific activation of transposons.

Prospects for the study of transposons in the pathogenesis of autoimmune diseases

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.

Genome-Wide Comparison of Structural Variations and Transposon Alterations in Soybean Cultivars Induced by Spaceflight.

Space mutation causes genetic and phenotypic changes in biological materials. Transposon activation is an adaptive mechanism for organisms to cope with changes in the external environment, such as space mutation. Although transposon alterations have been widely reported in diverse plant species, few studies have assessed the global transposon alterations in plants exposed to the space environment. In this study, for the first time, the effects of transposon alterations in soybean caused by space mutation were considered. A new vegetable soybean variety, 'Zhexian 9' (Z9), derived from space mutation treatment of 'Taiwan 75' (T75), was genetically analyzed. Comparative analyses of these two soybean genomes uncovered surprising structural differences, especially with respect to translocation breakends, deletions, and inversions. In total, 12,028 structural variations (SVs) and 29,063 transposable elements (TEs) between T75 and Z9 were detected. In addition, 1336 potential genes were variable between T75 and Z9 in terms of SVs and TEs. These differential genes were enriched in functions such as defense response, cell wall-related processes, epigenetics, auxin metabolism and transport, signal transduction, and especially methylation, which implied that regulation of epigenetic mechanisms and TE activity are important in the space environment. These results are helpful for understanding the role of TEs in response to the space environment and provide a theoretical basis for the selection of wild plant materials suitable for space breeding.

KCNQ1OT1 promotes genome-wide transposon repression by guiding RNA-DNA triplexes and HP1 binding.

Transposon (de)repression and heterochromatin reorganization are dynamically regulated during cell fate determination and are hallmarks of cellular senescence. However, whether they are sequence specifically regulated remains unknown. Here we uncover that the KCNQ1OT1 lncRNA, by sequence-specific Hoogsteen base pairing with double-stranded genomic DNA via its repeat-rich region and binding to the heterochromatin protein HP1α, guides, induces and maintains epigenetic silencing at specific repetitive DNA elements. Repressing KCNQ1OT1 or deleting its repeat-rich region reduces DNA methylation and H3K9me3 on KCNQ1OT1-targeted transposons. Engineering a fusion KCNQ1OT1 with an ectopically targeting guiding triplex sequence induces de novo DNA methylation at the target site. Phenotypically, repressing KCNQ1OT1 induces senescence-associated heterochromatin foci, transposon activation and retrotransposition as well as cellular senescence, demonstrating an essential role of KCNQ1OT1 to safeguard against genome instability and senescence.

DNA damage and repair in age-related inflammation.

Genomic instability is an important driver of ageing. The accumulation of DNA damage is believed to contribute to ageing by inducing cell death, senescence and tissue dysfunction. However, emerging evidence shows that inflammation is another major consequence of DNA damage. Inflammation is a hallmark of ageing and the driver of multiple age-related diseases. Here, we review the evidence linking DNA damage, inflammation and ageing, highlighting how premature ageing syndromes are associated with inflammation. We discuss the mechanisms by which DNA damage induces inflammation, such as through activation of the cGAS-STING axis and NF-κB activation by ATM. The triggers for activation of these signalling cascades are the age-related accumulation of DNA damage, activation of transposons, cellular senescence and the accumulation of persistent R-loops. We also discuss how epigenetic changes triggered by DNA damage can lead to inflammation and ageing via redistribution of heterochromatin factors. Finally, we discuss potential interventions against age-related inflammation.

Comprehensive analysis of both long and short read transcriptomes of a clonal and a seed-propagated model species reveal the prerequisites for transcriptional activation of autonomous and non-autonomous transposons in plants

BackgroundTransposable element (TE) transcription is a precursor to its mobilisation in host genomes. However, the characteristics of expressed TE loci, the identification of self-competent transposon loci contributing to new insertions, and the genomic conditions permitting their mobilisation remain largely unknown.ResultsUsing Vitis vinifera embryogenic callus, we explored the impact of biotic stressors on transposon transcription through the exposure of the callus to live cultures of an endemic grapevine yeast, Hanseniaspora uvarum. We found that only 1.7–2.5% of total annotated TE loci were transcribed, of which 5–10% of these were full-length, and the expressed TE loci exhibited a strong location bias towards expressed genes. These trends in transposon transcription were also observed in RNA-seq data from Arabidopsis thaliana wild-type plants but not in epigenetically compromised Arabidopsis ddm1 mutants. Moreover, differentially expressed TE loci in the grapevine tended to share expression patterns with co-localised differentially expressed genes. Utilising nanopore cDNA sequencing, we found a strong correlation between the inclusion of intronic TEs in gene transcripts and the presence of premature termination codons in these transcripts. Finally, we identified low levels of full-length transcripts deriving from structurally intact TE loci in the grapevine model.ConclusionOur observations in two disparate plant models representing clonally and seed propagated plant species reveal a closely connected transcriptional relationship between TEs and co-localised genes, particularly when epigenetic silencing is not compromised. We found that the stress treatment alone was insufficient to induce large-scale full-length transcription from structurally intact TE loci, a necessity for non-autonomous and autonomous mobilisation.

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.

Activation of DNA Transposons and Evolution of piRNA Genes Through Interspecific Hybridization in Xenopus Frogs.

Interspecific hybridization between two closely related species sometimes resulted in a new species with allotetraploid genomes. Many clawed frog species belonging to the Xenopus genus have diverged from the allotetraploid ancestor created by the hybridization of two closely related species with the predicted L and S genomes. There are species-specific repeated sequences including transposable elements in each genome of organisms that reproduce sexually. To understand what happened on and after the hybridization of the two distinct systems consisting of repeated sequences and their corresponding piRNAs, we isolated small RNAs from ovaries and testes of three Xenopus species consisting of allotetraploid X. laevis and X. borealis and diploid X. tropicalis as controls. After a comprehensive sequencing and selection of piRNAs, comparison of their sequences showed that most piRNA sequences were different between the ovaries and testes in all three species. We compared piRNA and genome sequences and specified gene clusters for piRNA expression in each genome. The synteny and homology analyses showed many distinct piRNA clusters among the three species and even between the two L and/or S subgenomes, indicating that most clusters of the two allotetraploid species changed after hybridization. Moreover, evolutionary analysis showed that DNA transposons including Kolobok superfamily might get activated just after hybridization and then gradually inactivated. These findings suggest that some DNA transposons and their piRNAs might greatly influence allotetraploid genome evolution after hybridization.

Influence of retroelements on oncogenes and tumor suppressors in carcinogenesis: A review

Analysis of scientific literature data has revealed several ways in which retrotransposons, when activated, are involved in carcinogenesis. First, retroelements can encode oncogenic proteins. For example, the Np9 protein is translated from HERV-K endogenous retrovirus transcript. Second, retroelements are used as alternative promoters of protooncogenes. Accordingly, their activation contributes to the enhanced expression of oncogenes (e.g. CSF1R, IRF5, MET, RAB3IP, CHRM3). Third, retroelements are located in the introns of some genes, and upon their activation, they form chimeric transcripts, such as LTR2-FABP7, LTR-ALK, LTR-ERBB4, LINE1-MET, which have pronounced oncogenic activity. Fourth, retroelements are transposed into tumor suppressor genes (e.g. APC, NF1, MSH2, PTEN, RB1, TSC2, STK11, VHL) and inactivate them, which is associated with the presence of hot spots of insertional mutagenesis in them. As a result, the growth of tumors and the survival of their cells are stimulated. It is important to note that protein products of tumor suppressor genes, such as TP53, RB1, VHL, BRCA1, ATM, are characterized by the ability to inhibit the activity of retroelements. Accordingly, when even one oncosuppressive gene is inactivated, a kind of "vicious circle" can be triggered when the control of expression of retroelements is weakened. The latter, in turn, inactivate other tumor suppressors containing hot spots of insertional mutagenesis. This stimulates new pathways of carcinogenesis and the production of oncogenes associated with transposons. Thus, it is possible to explain in a new way the mechanisms of tumor formation in hereditary tumor syndromes. This is due to the fact that the weakening of the function of an oncosuppressor in a germinal heterozygous mutation may be sufficient to trigger a vicious circle involving retroelements, oncogenes and other oncosuppressors. Similar mechanisms are likely for sporadic malignant tumors. However, the initiating event in them can be the direct activation of transposons under the influence of stressors, chemical and physical carcinogens. In addition to the events described, activation of retroelements causes genomic instability, which contributes to complex genomic rearrangements often observed in malignant tumors. MicroRNAs and long noncoding RNAs, the sources of which are retroelements, also play an important role in the evolution of tumors. Their study is promising for the development of targeted therapy for neoplasms.

Transposon-taming piRNAs in the germline: Where do they come from?

Mutations in the piRNA pathway protein components lead to transposon activation and fertility defects. In contrast, Gebert etal., (2021) saw no defects in transposon silencing or fertility when they deleted three large germline piRNA clusters in D.melanogaster.