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De novo DNA methylation (DNAme) during mouse oogenesis occurs within transcribed regions enriched for H3K36me3. As many oocyte transcripts originate in long terminal repeats (LTRs), which are heterogeneous even between closely related mammals, we examined whether species-specific LTR-initiated transcription units (LITs) shape the oocyte methylome. Here we identify thousands of syntenic regions in mouse, rat, and human that show divergent DNAme associated with private LITs, many of which initiate in lineage-specific LTR retrotransposons. Furthermore, CpG island (CGI) promoters methylated in mouse and/or rat, but not human oocytes, are embedded within rodent-specific LITs and vice versa. Notably, at a subset of such CGI promoters, DNAme persists on the maternal genome in fertilized and parthenogenetic mouse blastocysts or in human placenta, indicative of species-specific epigenetic inheritance. Polymorphic LITs are also responsible for disparate DNAme at promoter CGIs in distantly related mouse strains, revealing that LITs also promote intra-species divergence in CGI DNAme. De novo DNA methylation during mouse oogenesis occurs within transcribed regions. Here the authors investigate the role of species-specific long terminal repeats (LTRs)-initiated transcription units in regulating the oocyte methylome, identifying syntenic regions in mouse, rat and human with divergent DNA methylation associated with private LITs.

Telomere length maintenance is essential for most eukaryotes to ensure genome stability and integrity. A non-long terminal repeat (LTR) retrotransposon, SART1Bm, targets telomeric repeats (TTAGG)n of the silkworm Bombyx mori and is presumably involved in telomere length maintenance. However, how many telomeric repeats are required for its retrotransposition and how reverse transcription is initiated at the target site are not well understood. Here, using an ex vivo and trans-in vivo recombinant baculovirus retrotransposition system, we demonstrated that SART1Bm requires at least three (TTAGG) telomeric repeats and a longer poly(A) tail for its accurate retrotransposition. We found that SART1Bm retrotransposed only in the third (TTAGG) tract of three repeats and that the A residue of the (TTAGG) unit was essential for its retrotransposition. Interestingly, SART1Bm also retrotransposed into telomeric repeats of other species, such as human (TTAGGG)n repeats, albeit with low retrotransposition efficiency. We further showed that the reverse transcription of SART1Bm occurred inaccurately at the internal site of the 3′ untranslated region (UTR) when using a short poly(A) tail but at the accurate site when using a longer poly(A) tail. These findings promote our understanding of the general mechanisms of site-specific retrotransposition and aid the development of a site-specific gene knock-in tool.

Human endogenous retroviruses (HERVs) and other long terminal repeat (LTR)-type retrotransposons (HERV/LTRs) have regulatory elements that possibly influence the transcription of host genes. We systematically identified and characterized these regulatory elements based on publicly available datasets of ChIP-Seq of 97 transcription factors (TFs) provided by ENCODE and Roadmap Epigenomics projects. We determined transcription factor-binding sites (TFBSs) using the ChIP-Seq datasets and identified TFBSs observed on HERV/LTR sequences (HERV-TFBSs). Overall, 794,972 HERV-TFBSs were identified. Subsequently, we identified \"HERV/LTR-shared regulatory element (HSRE),\" defined as a TF-binding motif in HERV-TFBSs, shared within a substantial fraction of a HERV/LTR type. HSREs could be an indication that the regulatory elements of HERV/LTRs are present before their insertions. We identified 2,201 HSREs, comprising specific associations of 354 HERV/LTRs and 84 TFs. Clustering analysis showed that HERV/LTRs can be grouped according to the TF binding patterns; HERV/LTR groups bounded to pluripotent TFs (e.g., SOX2, POU5F1, and NANOG), embryonic endoderm/mesendoderm TFs (e.g., GATA4/6, SOX17, and FOXA1/2), hematopoietic TFs (e.g., SPI1 (PU1), GATA1/2, and TAL1), and CTCF were identified. Regulatory elements of HERV/LTRs tended to locate nearby and/or interact three-dimensionally with the genes involved in immune responses, indicating that the regulatory elements play an important role in controlling the immune regulatory network. Further, we demonstrated subgroup-specific TF binding within LTR7, LTR5B, and LTR5_Hs, indicating that gains or losses of the regulatory elements occurred during genomic invasions of the HERV/LTRs. Finally, we constructed dbHERV-REs, an interactive database of HERV/LTR regulatory elements (http://herv-tfbs.com/). This study provides fundamental information in understanding the impact of HERV/LTRs on host transcription, and offers insights into the transcriptional modulation systems of HERV/LTRs and ancestral HERVs.

Key Points Vertebrate genomes host a vast number of endogenous retroelements that exhibit distinct genomic structure, open reading frame integrity and replication autonomy or capability. Certain endogenous retroelement features have been retained to serve important immunological and non-immunological functions in the host. However, retention of 'viral' characteristics renders endogenous retroelements immunogenic. Despite targeted epigenetic silencing, many endogenous retroelements are still transcribed in adult cells and tissues. Such expression is strongly modulated in immune cells, particularly by immune stimuli. Endogenous retroelement-derived nucleic acids activate innate immune pathways, which contributes to pathologies such as systemic lupus erythematosus and Aicardi–Goutières syndrome. It also enhances responses to poorly immunogenic antigens, such as T cell-independent type 2 antigens or tumours. T cell and B cell responses to endogenous retroelement proteins are frequently detected. These adaptive responses contribute to the development of autoimmunity, but they can also lead to the targeting of abnormal cells, such as tumour cells, for destruction. Induction of endogenous retroelements by commensal colonization, pathogenic infection or cellular transformation may have evolved as an intrinsic warning system. Such beneficial contributions of immune reactivity to endogenous retroelements balance their pathogenic potential. A substantial proportion of our genome is composed of endogenous retroelements of viral origin. Such elements can retain viral characteristics and drive activation of the immune system; this can contribute to both undesirable outcomes, such as autoimmune disease, as well as beneficial responses, such as increased immune reactivity to tumours. In this Review, the authors describe the pros and the cons of these 'enemies within'. The ultimate form of parasitism and evasion of host immunity is for the parasite genome to enter the germ line of the host species. Retroviruses have invaded the host germ line on the grandest scale, and this is evident in the extraordinary abundance of endogenous retroelements in the genome of all vertebrate species that have been studied. Many of these endogenous retroelements have retained viral characteristics; some also the capacity to replicate and, consequently, the potential to trigger host innate and adaptive immune responses. However, although retroelements are mainly recognized for their pathogenic potential, recent evidence suggests that this 'enemy within' may also have beneficial roles in tuning host immune reactivity. In this Review, we discuss how the immune system recognizes and is shaped by endogenous retroelements.

• Transposable elements (TEs) are the main reason for the high plasticity of plant genomes, where they occur as communities of diverse evolutionary lineages. Because research has typically focused on single abundant families or summarized TEs at a coarse taxonomic level, our knowledge about how these lineages differ in their effects on genome evolution is still rudimentary. • Here we investigate the community composition and dynamics of 32 long terminal repeat retrotransposon (LTR-RT) families in the 272-Mb genome of the Mediterranean grass Brachypodium distachyon. • We find that much of the recent transpositional activity in the B. distachyon genome is due to centromeric Gypsy families and Copia elements belonging to the Angela lineage. With a half-life as low as 66 kyr, the latter are the most dynamic part of the genome and an important source of within-species polymorphisms. Second, GC-rich Gypsy elements of the Retand lineage are the most abundant TEs in the genome. Their presence explains > 20% of the genome-wide variation in GC content and is associated with higher methylation levels. • Our study shows how individual TE lineages change the genetic and epigenetic constitution of the host beyond simple changes in genome size.

Background: The mobilization of transposable elements (TEs) is suppressed by host genome defense mechanisms. Recent studies showed that the cis-regulatory region of Arabidopsis thaliana COPIA78/ONSEN retrotransposons contains heat-responsive elements (HREs), which cause their activation during heat stress. However, it remains unknown whether this is a common and potentially conserved trait and how it has evolved. Results: We show that ONSEN, COPIA37, TERESTRA, and ROMANIAT5 are the major families of heat-responsive TEs in A. lyrata and A. thaliana. Heat-responsiveness of COPIA families is correlated with the presence of putative high affinity heat shock factor binding HREs within their long terminal repeats in seven Brassicaceae species. The strong HRE of ONSEN is conserved over millions of years and has evolved by duplication of a proto-HRE sequence, which was already present early in the evolution of the Brassicaceae. However, HREs of most families are species-specific, and in Boechera stricta, the ONSEN HRE accumulated mutations and lost heat-responsiveness. Conclusions: Gain of HREs does not always provide an ultimate selective advantage for TEs, but may increase the probability of their long-term survival during the co-evolution of hosts and genomic parasites.

Background Miniature inverted-repeat transposable elements (MITEs) and long terminal repeat (LTR) retrotransposons are ubiquitous in plants genomes, and highly important in their evolution and diversity. However, their mechanisms of insertion/amplification and roles in Citrus genome’s evolution/diversity are still poorly understood. Results To address this knowledge gap, we developed different computational pipelines to analyze, annotate and classify MITEs and LTR retrotransposons in six different sequenced Citrus species. We identified 62,010 full-length MITEs from 110 distinguished families. We observed MITEs tend to insert in gene related regions and enriched in promoters. We found that DTM63 is possibly an active Mutator -like MITE family in the traceable past and may still be active in Citrus . The insertion of MITEs resulted in massive polymorphisms and played an important role in Citrus genome diversity and gene structure variations. In addition, 6630 complete LTR retrotransposons and 13,371 solo-LTRs were identified. Among them, 12 LTR lineages separated before the differentiation of mono- and dicotyledonous plants. We observed insertion and deletion of LTR retrotransposons was accomplished with a dynamic balance, and their half-life in Citrus was ~ 1.8 million years. Conclusions These findings provide insights into MITEs and LTR retrotransposons and their roles in genome diversity in different Citrus genomes.

Key messageWe briefly discuss that the similarity of LTR retrotransposons to retroviruses is a great opportunity for the development of a genetic engineering tool that exploits intragenic elements in the plant genome for plant genetic improvement.Long terminal repeat (LTR) retrotransposons are very similar to retroviruses but do not have the property of being infectious. While spreading between its host cells, a retrovirus inserts a DNA copy of its genome into the cells. The ability of retroviruses to cause infection with genome integration allows genes to be delivered to cells and tissues. Retrovirus vectors are, however, only specific to animals and insects, and, thus, are not relevant to plant genetic engineering. However, the similarity of LTR retrotransposons to retroviruses is an opportunity to explore the former as a tool for genetic engineering. Although recent long-read sequencing technologies have advanced the knowledge about transposable elements (TEs), the integration of TEs is still unable either to control them or to direct them to specific genomic locations. The use of existing intragenic elements to achieve the desired genome composition is better than using artificial constructs like vectors, but it is not yet clear how to control the process. Moreover, most LTR retrotransposons are inactive and unable to produce complete proteins. They are also highly mutable. In addition, it is impossible to find a full active copy of a LTR retrotransposon out of thousands of its own copies. Theoretically, if these elements were directly controlled and turned on or off using certain epigenetic mechanisms (inducing by stress or infection), LTR retrotransposons could be a great opportunity to develop a genetic engineering tool using intragenic elements in the plant genome. In this review, the recent developments in uncovering the nature of LTR retrotransposons and the possibility of using these intragenic elements as a tool for plant genetic engineering are briefly discussed.

Recent studies have demonstrated the important role of plant microRNAs (miRNAs) under nutrient deficiencies. In this study, deep sequencing of Arabidopsis (Arabidopsis thaliana) small RNAs was conducted to reveal miRNAs and other small RNAs that were differentially expressed in response to phosphate (Pi) deficiency. About 3.5 million sequence reads corresponding to 0.6 to 1.2 million unique sequence tags from each Pi-sufficient or Pi-deficient root or shoot sample were mapped to the Arabidopsis genome. We showed that upon Pi deprivation, the expression of miR156, miR399, miR778, miR827, and miR2111 was induced, whereas the expression of miR169, miR395, and miR398 was repressed. We found cross talk coordinated by these miRNAs under different nutrient deficiencies. In addition to miRNAs, we identified one Pi starvation-induced DICER-LIKE1-dependent small RNA derived from the long terminal repeat of a retrotransposon and a group of 19-nucleotide small RNAs corresponding to the 5' end of tRNA and expressed at a high level in Pi-starved roots. Importantly, we observed an increased abundance of TAS4-derived trans-acting small interfering RNAs (ta-siRNAs) in Pi-deficient shoots and uncovered an autoregulatory mechanism of PAP1/MYB75 via miR828 and TAS4-siR81(-) that regulates the biosynthesis of anthocyanin. This finding sheds light on the regulatory network between miRNA/ta-siRNA and its target gene. Of note, a substantial amount of miR399* accumulated under Pi deficiency. Like miR399, miR399* can move across the graft junction, implying a potential biological role for miR399*. This study represents a comprehensive expression profiling of Pi-responsive small RNAs and advances our understanding of the regulation of Pi homeostasis mediated by small RNAs.

Endogenous retroviruses (ERVs) are genetic elements present in the genome that retain traces of past viral infections. Characterization of ERVs can provide crucial insights into avian evolution. This study aimed to identify novel long terminal repeat (LTR) loci derived from ERVs (ERV-LTRs) absent in the reference genome using whole-genome sequencing data of red junglefowl, gray junglefowl, Ceylon junglefowl, and green junglefowl. In total, 835 ERV-LTR loci were identified across the four Gallus species. The numbers of ERV-LTRs loci detected in red junglefowl and its subspecies gray junglefowl, Ceylon junglefowl, and green junglefowl were 362, 216, 193, and 128, respectively. The phylogenetic tree was congruent with previously reported trees, suggesting the potential for inferring relationships among past junglefowl populations from the identified ERV-LTR loci. Of the detected loci, 306 ERV-LTRs were identified near or within the genes, and some were associated with cell adhesion. The detected ERV-LTR sequences were classified as endogenous avian retrovirus family, avian leukosis virus subgroup E, Ovex-1, and murine leukemia virus-related ERVs. In addition, the sequence of the EAV family was divided into four patterns by combining the U3, R, and U5 regions. These findings contribute to a more comprehensive understanding of the characteristics of junglefowl ERVs.