Transposable Element Genes Research Articles

Association of hyperactivated transposon expression with exacerbated immune activation in systemic lupus erythematosus

BackgroundSystemic Lupus Erythematosus (SLE) is a complex autoimmune disorder, and transposable elements (TEs) have been hypothesized to play a significant role in its development. However, limited research has explored this connection. Our study aimed to examine the relationship between TE expression and SLE pathogenesis.MethodsWe analyzed whole blood RNA-seq datasets from 198 SLE patients and 84 healthy controls. The REdiscoverTE pipeline was employed to quantify TE and other gene expressions, identifying differentially expressed TEs. A TE score was calculated to measure overall TE expression for each sample. Gene ontology and gene set enrichment analyses were conducted to explore the functional implications of TE upregulation. Independent datasets were utilized to replicate the results and investigate cell type-specific TE expression.ResultsOur analysis identified two distinct patient groups: one with high TE expression and another with TE expression comparable to controls. Patients with high TE expression exhibited upregulation of pathways involving nucleic acid sensors, and TE expression was strongly correlated with interferon (IFN) signatures. Furthermore, these patients displayed deregulated cell composition, including increased neutrophils and decreased regulatory T cells. Neutrophils were suggested as the primary source of TE expression, contributing to IFN production.ConclusionsOur findings suggest that TE expression may serve as a crucial mediator in maintaining the activation of interferon pathways, acting as an endogenous source of nucleic acid stimulators in SLE patients.

Harnessing transposable elements for cancer therapy

Transposable elements (TEs) can move within the genome and can have a significant role in cancer development. Shah et al. recently identified that TEs have regulatory potentials and that tumor-specific TE–gene chimeric events that produce new isoforms of proteins could serve as universal cancer biomarkers and targets for cancer immunotherapy.

Genome-wide identification and characterization of exapted transposable elements in the large genome of sunflower (Helianthus annuus L.).

Transposable elements (TEs) are an important source of genome variability, playing many roles in the evolution of eukaryotic species. Besides well-known phenomena, TEs may undergo the exaptation process and generate the so-called exapted transposable element genes (ETEs). Here we present a genome-wide survey of ETEs in the large genome of sunflower (Helianthus annuus L.), in which the massive amount of TEs, provides a significant source for exaptation. A library of sunflower TEs was used to build TE-specific Hidden Markov Model profiles, to search for all available sunflower gene products. In doing so, 20 016 putative ETEs were identified and further investigated for the characteristics that distinguish TEs from genes, leading to the validation of 3530 ETEs. The analysis of ETEs transcription patterns under different stress conditions showed a differential regulation triggered by treatments mimicking biotic and abiotic stress; furthermore, the distribution of functional domains of differentially regulated ETEs revealed a relevant presence of domains involved in many aspects of cellular functions. A comparative genomic investigation was performed including species representative of Asterids and appropriate outgroups: the bulk of ETEs that resulted were specific to the sunflower, while few ETEs presented orthologues in the genome of all analyzed species, making the hypothesis of a conserved function. This study highlights the crucial role played by exaptation, actively contributing to species evolution.

Transposable elements

Transposable elements are known by many names, including 'transposons', 'interspersed repeats', 'selfish genetic elements', 'jumping genes', and 'parasitic DNA', but here we will refer to them simply as transposable elements. Many biologists will have heard of transposable elements and their ability to transpose (change position) within the genome. But fewer may be aware of their varied influences on host biology, including contributions to the evolution of diverse host traits such as internal gestation, memory, colouration, and adaptive immunity. Transposable elements are a near ubiquitous feature of eukaryotic genomes, and they often comprise a substantial proportion of total genomic content. Consequently, transposable element genes are considered among the most abundant coding sequences in nature. Recent advances in genome sequencing have ushered in a golden age for transposable-element research, providing opportunities to greatly improve our understanding of the effects of transposable elements on host evolution and disease. However, our ability to detect and analyse transposable elements still faces significant challenges, impairing efforts to decipher their evolution, characterise their diversity, and elucidate their myriad host influences. Below, we summarise key aspects of transposable element biology in eukaryotes and discuss major outstanding research questions.

A transposon expression burst accompanies the activation of Y-chromosome fertility genes during Drosophila spermatogenesis

Transposable elements (TEs) must replicate in germline cells to pass novel insertions to offspring. In Drosophila melanogaster ovaries, TEs can exploit specific developmental windows of opportunity to evade host silencing and increase their copy numbers. However, TE activity and host silencing in the distinct cell types of Drosophila testis are not well understood. Here, we reanalyze publicly available single-cell RNA-seq datasets to quantify TE expression in the distinct cell types of the Drosophila testis. We develop a method for identification of TE and host gene expression modules and find that a distinct population of early spermatocytes expresses a large number of TEs at much higher levels than other germline and somatic components of the testes. This burst of TE expression coincides with the activation of Y chromosome fertility factors and spermatocyte-specific transcriptional regulators, as well as downregulation of many components of the piRNA pathway. The TEs expressed by this cell population are specifically enriched on the Y chromosome and depleted on the X chromosome, relative to other active TEs. These data suggest that some TEs may achieve high insertional activity in males by exploiting a window of opportunity for mobilization created by the activation of spermatocyte-specific and Y chromosome-specific transcriptional programs.

English

Smallholder dairy cattle rumen microbiotas are subjected to a wide range of antimicrobials as well as sudden fluctuations in diets. As such, they develop an enormous reservoir of resistant genes, mobilome and stress response genes. However, information on metagenomic reactions to such dietary variations, especially for cattle reared in the tropics, remains largely unexplored. This meta-analysis was conducted to assess if antibiotic and toxic compound resistance genes (ARGs), stress response genes and bacterial phages, prophages and transposable element genes were present, and to what extent, in three dairy cattle genotypes (Friesian, FriesianXJersey crossbreed, Jersey) reared in a farm that practiced judicious use of antimicrobials. Potential bacterial hosts to these genes were also explored. The rumen metagenomes generated from Next Generation Sequencing (NGS) technology were analyzed using MG-RAST. According to the results stress reaction, resistance and mobilome genes were present in similar amounts in all the three genotypes. Cobalt-zinc-cadmium resistance, fluoroquinolone resistance, methicillin resistance in Staphylococci and multidrug resistance efflux pumps were the most abundant resistant genes and were spread across 20, 24, 16 and 21 bacterial classes, respectively. Bacteria in charge of phage integration and excision, phages replication and phage packaging were mostly allocated to the phyla Firmicutes, Bacteroides and Proteobacteria. Within the stress response genes, metagenomic assembly-based host-tracking analysis identified the extended heat shock dnaK gene cluster as the most abundant genes, while Bacteroides and Clostridium were the principal bacterial hosts. The results show that even with proper use of antimicrobials, the cattle rumen contained an immense distribution of responses to stress, ARGs and mobilome genes distributed in a vast assemblage of hosts. There is also a high correlation between these three functional groups. Key words: Resistome, metagenome, MG-RAST, Stress genes, mobilome

RNA interference-independent reprogramming of DNA methylation in Arabidopsis.

DNA methylation is important for silencing transposable elements (TEs) in diverse eukaryotes, including plants. In plant genomes, TEs are silenced by methylation of histone H3 lysine 9 (H3K9) and cytosines in both CG and non-CG contexts. The role of RNA interference (RNAi) in establishing TE-specific silent marks has been extensively studied, but the importance of RNAi-independent pathways remains largely unexplored. Here, we directly investigated transgenerational de novo DNA methylation of TEs after the loss of silent marks. Our analyses uncovered potent and precise RNAi-independent pathways for recovering non-CG methylation and H3K9 methylation in most TE genes (that is, coding regions within TEs). Characterization of a subset of TE genes without the recovery revealed the effects of H3K9 demethylation, replacement of histone H2A variants and their interaction with CG methylation, together with feedback from transcription. These chromatin components are conserved among eukaryotes and may contribute to chromatin reprogramming in a conserved manner.

Disrupting the disruptors: the consequences of mutations in mobile elements for ecologically important life history traits

Transposable elements are a nearly ubiquitous component of eukaryotic genomes. While often described as parasitic genetic elements, other evidence suggests that transposable elements can become domesticated and contribute to organismal function. There is little empirical data on the positive or negative contribution of transposable elements to organismal traits. We hypothesized that mutations in transposable element genes would have less deleterious effects than mutations in other plant genes. We conducted an assay of phenotypes associated with growth and reproduction in a collection of insertion mutation lines in Arabidopsis thaliana that disrupted the sequence of a transposable element gene. The transposable element loci were from locations dispersed across the genome, and included loci from several element families. Overall, we found that mutants in transposable element genes were similar to mutants in other types of loci for the measured traits, in most cases with a distribution of effects centered on life history trait values of wild-type plants critical to population ecology processes. If transposable elements are predominantly parasitic, their deleterious effects were not uncovered by these disruptive mutations. Further characterization of the positive, negative or neutral contribution of transposable element sequences would address unresolved questions about the contribution of transposition and selection to genome evolution.

Comparative analysis of genome-wide DNA methylation in Neurospora

ABSTRACT DNA methylation is an epigenetic mark that plays an important role in genetic regulation in eukaryotes. Major progress has been made in dissecting the molecular pathways that regulate DNA methylation. Yet, little is known about DNA methylation variation over evolutionary time. Here we present an investigation of the variation of DNA methylation and transposable element (TE) content in species of the filamentous ascomycetes Neurospora. We generated genome-wide DNA methylation data at single-base resolution, together with genomic TE content and gene expression data, of 10 individuals representing five closely related Neurospora species. We found that the methylation levels were low (ranging from 1.3% to 2.5%) and varied among the genomes in a species-specific way. Furthermore, we found that the TEs over 400 bp long were targeted by DNA methylation, and in all genomes, high methylation correlated with low GC, confirming a conserved link between DNA methylation and Repeat Induced Point (RIP) mutations in this group of fungi. Both TE content and DNA methylation pattern showed phylogenetic signal, and the species with the highest TE load (N. crassa) also exhibited the highest methylation level per TE. Our results suggest that DNA methylation is an evolvable trait and indicate that the genomes of Neurospora are shaped by an evolutionary arms race between TEs and host defence.

Transposon activation is a major driver in the genome evolution of cultivated olive trees (Olea europaea L.).

The primary domestication of olive (Olea europaea L.) in the Levant dates back to the Neolithic period, around 6,000-5,500 BC, as some archeological remains attest. Cultivated olive trees are reproduced clonally, with sexual crosses being the sporadic events that drive the development of new varieties. In order to determine the genomic changes which have occurred in a modern olive cultivar, the genome of the Picual cultivar, one of the most popular olive varieties, was sequenced. Additional 40 cultivated and 10 wild accessions were re-sequenced to elucidate the evolution of the olive genome during the domestication process. It was found that the genome of the 'Picual' cultivar contains 79,667 gene models, of which 78,079 were protein-coding genes and 1,588 were tRNA. Population analyses support two independent events in olive domestication, including an early possible genetic bottleneck. Despite genetic bottlenecks, cultivated accessions showed a high genetic diversity driven by the activation of transposable elements (TE). A high TE gene expression was observed in presently cultivated olives, which suggests a current activity of TEs in domesticated olives. Several TEs families were expanded in the last 5,000 or 6,000 years and produced insertions near genes that may have been involved in selected traits during domestication as reproduction, photosynthesis, seed development, and oil production. Therefore, a great genetic variability has been found in cultivated olive as a result of a significant activation of TEs during the domestication process.

TEffectR: an R package for studying the potential effects of transposable elements on gene expression with linear regression model.

IntroductionRecent studies highlight the crucial regulatory roles of transposable elements (TEs) on proximal gene expression in distinct biological contexts such as disease and development. However, computational tools extracting potential TE –proximal gene expression associations from RNA-sequencing data are still missing.ImplementationHerein, we developed a novel R package, using a linear regression model, for studying the potential influence of TE species on proximal gene expression from a given RNA-sequencing data set. Our R package, namely TEffectR, makes use of publicly available RepeatMasker TE and Ensembl gene annotations as well as several functions of other R-packages. It calculates total read counts of TEs from sorted and indexed genome aligned BAM files provided by the user, and determines statistically significant relations between TE expression and the transcription of nearby genes under diverse biological conditions.AvailabilityTEffectR is freely available at https://github.com/karakulahg/TEffectR along with a handy tutorial as exemplified by the analysis of RNA-sequencing data including normal and tumour tissue specimens obtained from breast cancer patients.

A genomic survey of transposable elements in the choanoflagellate Salpingoeca rosetta reveals selection on codon usage

BackgroundUnicellular species make up the majority of eukaryotic diversity, however most studies on transposable elements (TEs) have centred on multicellular host species. Such studies may have therefore provided a limited picture of how transposable elements evolve across eukaryotes. The choanoflagellates, as the sister group to Metazoa, are an important study group for investigating unicellular to multicellular transitions. A previous survey of the choanoflagellate Monosiga brevicollis revealed the presence of only three families of LTR retrotransposons, all of which appeared to be active. Salpingoeca rosetta is the second choanoflagellate to have its whole genome sequenced and provides further insight into the evolution and population biology of transposable elements in the closest relative of metazoans.ResultsScreening the genome revealed the presence of a minimum of 20 TE families. Seven of the annotated families are DNA transposons and the remaining 13 families are LTR retrotransposons. Evidence for two putative non-LTR retrotransposons was also uncovered, but full-length sequences could not be determined. Superfamily phylogenetic trees indicate that vertical inheritance and, in the case of one family, horizontal transfer have been involved in the evolution of the choanoflagellates TEs. Phylogenetic analyses of individual families highlight recent element activity in the genome, however six families did not show evidence of current transposition. The majority of families possess young insertions and the expression levels of TE genes vary by four orders of magnitude across families. In contrast to previous studies on TEs, the families present in S. rosetta show the signature of selection on codon usage, with families favouring codons that are adapted to the host translational machinery. Selection is stronger in LTR retrotransposons than DNA transposons, with highly expressed families showing stronger codon usage bias. Mutation pressure towards guanosine and cytosine also appears to contribute to TE codon usage.ConclusionsS. rosetta increases the known diversity of choanoflagellate TEs and the complement further highlights the role of horizontal gene transfer from prey species in choanoflagellate genome evolution. Unlike previously studied TEs, the S. rosetta families show evidence for selection on their codon usage, which is shown to act via translational efficiency and translational accuracy.

Identification of miRNA, their targets and miPEPs in peanut (Arachis hypogaea L.)

MicroRNAs (miRNAs) are one of the major cytoplasmic tools employed by the eukaryotes for post-transcriptional gene regulation. These ˜21 nt small non-coding RNA molecules are highly conserved among species which forms a base for identification of new miRNAs. In this study, we used previously known mature miRNAs to search their homologs in Arachis hypogaea ESTs. A total of 50 non-protein coding sequences showing homology with no more than 3 mismatches were folded back to hairpin stem-loop structures using mfold. These predicted structures were passed through strict filtration criteria to obtain 18 miRNAs, all of which were other than those reported in miRBase. Out of 18 miRNAs, 7 were found to be new. These miRNAs belonged to miR156, miR166, miR167, miR319, miR398, miR399, miR482 and miR1507 family. These miRNAs were found to target a total of 118 genes in Arabidopsis. These targets included disease resistant proteins, auxin responsive proteins, squamosa promoter binding like proteins, co-transporter protein, transposable element genes, NAD(P) binding protein and topoisomerase II. KEGG pathway analysis showed potential involvement of these miRNAs in regulating different pathways. Apart from miRNA and their targets, microRNA encoded peptides (miPEPs) for 14 miRNAs were also identified. These findings can be used in the appropriate manipulation of miRNAs and corresponding miPEPs that will be helpful towards the peanut crop improvement.

Novel Insights into Plant Genome Evolution and Adaptation as Revealed through Transposable Elements and Non-Coding RNAs in Conifers.

Plant genomes are punctuated by repeated bouts of proliferation of transposable elements (TEs), and these mobile bursts are followed by silencing and decay of most of the newly inserted elements. As such, plant genomes reflect TE-related genome expansion and shrinkage. In general, these genome activities involve two mechanisms: small RNA-mediated epigenetic repression and long-term mutational decay and deletion, that is, genome-purging. Furthermore, the spatial relationships between TE insertions and genes are an important force in shaping gene regulatory networks, their downstream metabolic and physiological outputs, and thus their phenotypes. Such cascading regulations finally set up a fitness differential among individuals. This brief review demonstrates factual evidence that unifies most updated conceptual frameworks covering genome size, architecture, epigenetic reprogramming, and gene expression. It aims to give an overview of the impact that TEs may have on genome and adaptive evolution and to provide novel insights into addressing possible causes and consequences of intimidating genome sizes (20–30 Gb) in a taxonomic group, conifers.

Comparative Analysis of Flanking Sequence Tags of T-DNA/Transposon Insertional Mutants and Genetic Variations of Fast-neutron Treated Mutants in Rice

Whole genome sequencing analyses of 1,504 fast-neutron (FN)-induced mutants of ‘Kitaake’ rice variety have revealed a new mutant population covering 58.6% of transposable element (TE) genes and 47.6% of non-TE genes throughout the rice genome. Mutation rate for TE gene is much higher in FN-induced mutants (58.6%) than in flanking sequence tag (FST) population (25.7%), implying that the former are more randomly generated than the latter. By adding this resource to FST population, we found that the mutation rate for the rice genome increases from 53.1% to 78.1% and more importantly, the rate with multiple alleles increases from 35.2% to 56.1%. To test the functional significance of mutants produced by both FN-induction and T-DNA/transposon insertions, we analyzed the coverage of functionally characterized genes by using the Overview of functionally characterized Genes in Rice Online database (OGRO, http://qtaro.abr.affrc.go.jp/ogro/table). These combined genetic resources cover the mutations for 90.9% of functionally characterized genes for morphological traits, 91.0% for physiological traits, and 92.6% for resistance or tolerance traits, indicating that a gene-indexed mutant population that includes FN-induced mutants is valuable to future research for improving most of the important agronomic traits.

Senescent human hematopoietic progenitors show elevated expression of transposable elements and inflammatory genes

Genomic transposable elements (TEs) constitute the majority of the genome. Expression of TEs is known to activate the double-stranded RNA recognition pathway ("viral mimicry"), leading to the activation of interferon-stimulated genes, inflammation, and immune-mediated cell death. Recently, we showed that the expression of TEs is suppressed along with immune pathways in leukemic stem cells (LSCs) in acute myeloid leukemia, suggesting a potential mechanism for immune escape of LSCs. This indicated that, during oncogenesis, where there is escape from senescence, expression of TEs is suppressed. Senescence is known to activate the interferon response and inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). We characterized the transcriptome of senescent and active human hematopoietic stem and progenitor cells (HSPCs) in vivo and showed co-occurrence of overexpression of TEs, SASP genes, and gene pathways of inflammation in senescence. The percentage of circulating senescent HSPCs (s-HSPCs) did not increase with age, indicating active clearance. Induction of senescence in human HSPCs in vitro showed increased expression of TE and SASP genes. SASP is known to mediate clearance of senescent cells and active clearance of senescent cells has been shown to increase organismal fitness. We speculate that the expression of TEs in s-HSPCs could contribute to orderly clearance of the cells via activation of immune pathways, warranting further mechanistic studies. This is the first study to characterize the transcriptome of human s-HSPCs in vivo, revealing activated expression of TEs and inflammatory genes.

Piecing together cis-regulatory networks: insights from epigenomics studies in plants.

5-Methylcytosine, a chemical modification of DNA, is a covalent modification found in the genomes of both plants and animals. Epigenetic inheritance of phenotypes mediated by DNA methylation is well established in plants. Most of the known mechanisms of establishing, maintaining and modifying DNA methylation have been worked out in the reference plant Arabidopsis thaliana. Major functions of DNA methylation in plants include regulation of gene expression and silencing of transposable elements (TEs) and repetitive sequences, both of which have parallels in mammalian biology, involve interaction with the transcriptional machinery, and may have profound effects on the regulatory networks in the cell. Methylome and transcriptome dynamics have been investigated in development and environmental responses in Arabidopsis and agriculturally and ecologically important plants, revealing the interdependent relationship among genomic context, methylation patterns, and expression of TE and protein coding genes. Analyses of methylome variation among plant natural populations and species have begun to quantify the extent of genetic control of methylome variation vs. true epimutation, and model the evolutionary forces driving methylome evolution in both short and long time scales. The ability of DNA methylation to positively or negatively modulate binding affinity of transcription factors (TFs) provides a natural link from genome sequence and methylation changes to transcription. Technologies that allow systematic determination of methylation sensitivities of TFs, in native genomic and methylation context without confounding factors such as histone modifications, will provide baseline datasets for building cell-type- and individual-specific regulatory networks that underlie the establishment and inheritance of complex traits. This article is categorized under: Laboratory Methods and Technologies > Genetic/Genomic Methods Biological Mechanisms > Regulatory Biology.

Evolutionary Epigenomics of Retrotransposon-Mediated Methylation Spreading in Rice.

Plant genomes contain numerous transposable elements (TEs), and many hypotheses on the evolutionary drivers that restrict TE activity have been postulated. Few models, however, have focused on the evolutionary epigenomic interaction between the plant host and its TE. The host genome recruits epigenetic factors, such as methylation, to silence TEs but methylation can spread beyond the TE sequence and influence the expression of nearby host genes. In this study, we investigated this epigenetic trade-off between TE and proximal host gene silencing by studying the epigenomic regulation of repressing long terminal repeat (LTR) retrotransposons (RTs) in Oryza sativa. Results showed significant evidence of methylation spreading originating from the LTR-RT sequences, and the extent of spreading was dependent on five factors: 1) LTR-RT family, 2) time since the LTR-RT insertion, 3) recombination rate of the LTR-RT region, 4) level of LTR-RT sequence methylation, and 5) chromosomal location. Methylation spreading had negative effects by reducing host gene expression, but only on host genes with LTR-RT inserted in its introns. Our results also suggested high levels of LTR-RT methylation might have a role in suppressing TE-mediated deleterious ectopic recombination. In the end, despite the methylation spreading, no strong epigenetic trade-off was detected and majority of LTR-RT may have only minor epigenetic effects on nearby host genes.

Nonrandom domain organization of the Arabidopsis genome at the nuclear periphery.

The nuclear space is not a homogeneous biochemical environment. Many studies have demonstrated that the transcriptional activity of a gene is linked to its positioning within the nuclear space. Following the discovery of lamin-associated domains (LADs), which are transcriptionally repressed chromatin regions, the nonrandom positioning of chromatin at the nuclear periphery and its biological relevance have been studied extensively in animals. However, it remains unknown whether comparable chromatin organizations exist in plants. Here, using a strategy using restriction enzyme–mediated chromatin immunoprecipitation, we present genome-wide identification of nonrandom domain organization of chromatin at the peripheral zone of Arabidopsis thaliana nuclei. We show that in various tissues, 10%–20% of the regions on the chromosome arms are anchored at the nuclear periphery, and these regions largely overlap between different tissues. Unlike LADs in animals, the identified domains in plants are not gene-poor or A/T-rich. These domains are enriched with silenced protein-coding genes, transposable element genes, and heterochromatic marks, which collectively define a repressed environment. In addition, these domains strongly correlate with our genome-wide chromatin interaction data set (Hi-C) by largely explaining the patterns of chromatin compartments, revealed on Hi-C maps. Moreover, our results reveal a spatial compartment of different DNA methylation pathways that regulate silencing of transposable elements, where the CHH methylation of transposable elements located at the nuclear periphery and in the interior are preferentially mediated by CMT2 and DRM methyltransferases, respectively. Taken together, the results demonstrate functional partitioning of the Arabidopsis genome in the nuclear space.

A Comparative Analysis of 5-Azacytidine- and Zebularine-Induced DNA Demethylation.

The nonmethylable cytosine analogs, 5-azacytidine and zebularine, are widely used to inhibit DNA methyltransferase activity and reduce genomic DNA methylation. In this study, whole-genome bisulfite sequencing is used to construct maps of DNA methylation with single base pair resolution in Arabidopsis thaliana seedlings treated with each demethylating agent. We find that both inhibitor treatments result in nearly indistinguishable patterns of genome-wide DNA methylation and that 5-azacytidine had a slightly greater demethylating effect at higher concentrations across the genome. Transcriptome analyses revealed a substantial number of upregulated genes, with an overrepresentation of transposable element genes, in particular CACTA-like elements. This demonstrates that chemical demethylating agents have a disproportionately large effect on loci that are otherwise silenced by DNA methylation.