Explore the vast range of titles available.

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.

Chromatin organization is essential for appropriate interpretation of the genetic information. Here, we demonstrated that the chromatin-associated proteins HP1 are dispensable for hepatocytes survival but are essential within hepatocytes to prevent liver tumor development in mice with HP1β being pivotal in these functions. Yet, we found that the loss of HP1 per se is not sufficient to induce cell transformation but renders cells more resistant to specific stress such as the expression of oncogenes and thus in fine, more prone to cell transformation. Molecular characterization of HP1-Triple KO premalignant livers and BMEL cells revealed that HP1 are essential for the maintenance of heterochromatin organization and for the regulation of specific genes with most of them having well characterized functions in liver functions and homeostasis. We further showed that some specific retrotransposons get reactivated upon loss of HP1, correlating with overexpression of genes in their neighborhood. Interestingly, we found that, although HP1-dependent genes are characterized by enrichment H3K9me3, this mark does not require HP1 for its maintenance and is not sufficient to maintain gene repression in absence of HP1. Finally, we demonstrated that the loss of TRIM28 association with HP1 recapitulated several phenotypes induced by the loss of HP1 including the reactivation of some retrotransposons and the increased incidence of liver cancer development. Altogether, our findings indicate that HP1 proteins act as guardians of liver homeostasis to prevent tumor development by modulating multiple chromatin-associated events within both the heterochromatic and euchromatic compartments, partly through regulation of the corepressor TRIM28 activity.

DNA cytosine methylation (5mC) is indispensable for a number of cellular processes, including retrotransposon silencing, genomic imprinting, and X chromosome inactivation in mammalian development. Recent studies have focused on 5-hydroxymethylcytosine (5hmC), a new epigenetic mark or intermediate in the DNA demethylation pathway. However, 5hmC itself has no role in pluripotency maintenance in mouse embryonic stem cells (ESCs) lacking Dnmt1 , 3a , and 3b . Here, we demonstrated that 5hmC accumulated on euchromatic chromosomal bands that were marked with di- and tri-methylated histone H3 at lysine 4 (H3K4me2/3) in mouse ESCs. By contrast, heterochromatin enriched with H3K9me3, including mouse chromosomal G-bands, pericentric repeats, human satellite 2 and 3, and inactive X chromosomes, was not enriched with 5hmC. Therefore, enzymes that hydroxylate the methyl group of 5mC belonging to the Tet family might be excluded from inactive chromatin, which may restrict 5mC to 5hmC conversion in euchromatin to prevent nonselective de novo DNA methylation.

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage–fusion–bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of 22 L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors. An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Increasing the proportion of locally produced plant protein in currently meat-rich diets could substantially reduce greenhouse gas emissions and loss of biodiversity1. However, plant protein production is hampered by the lack of a cool-season legume equivalent to soybean in agronomic value2. Faba bean (Vicia faba L.) has a high yield potential and is well suited for cultivation in temperate regions, but genomic resources are scarce. Here, we report a high-quality chromosome-scale assembly of the faba bean genome and show that it has expanded to a massive 13 Gb in size through an imbalance between the rates of amplification and elimination of retrotransposons and satellite repeats. Genes and recombination events are evenly dispersed across chromosomes and the gene space is remarkably compact considering the genome size, although with substantial copy number variation driven by tandem duplication. Demonstrating practical application of the genome sequence, we develop a targeted genotyping assay and use high-resolution genome-wide association analysis to dissect the genetic basis of seed size and hilum colour. The resources presented constitute a genomics-based breeding platform for faba bean, enabling breeders and geneticists to accelerate the improvement of sustainable protein production across the Mediterranean, subtropical and northern temperate agroecological zones.

Comprehensive and accurate annotation of the repeatome, including transposons, is critical for deepening our understanding of repeat origins, biogenesis, regulatory mechanisms, and roles. Here, we developed Generic Repeat Finder (GRF), a tool for genome-wide repeat detection based on fast, exhaustive numerical calculation algorithms integrated with optimized dynamic programming strategies. GRF sensitively identifies terminal inverted repeats (TIRs), terminal direct repeats (TDRs), and interspersed repeats that bear both inverted and direct repeats. GRF also detects DNA or RNA transposable elements characterized by these repeats in plant and animal genomes. For TIRs and TDRs, GRF identifies spacers in the middle and mismatches/insertions or deletions in terminal repeats, showing their alignment or base-pairing information. GRF helps improve the annotation for various DNA transposons and retrotransposons, such as miniature inverted-repeat transposable elements (MITEs), long terminal repeat (LTR) retrotransposons, and non-LTR retrotransposons, including long interspersed nuclear elements and short interspersed nuclear elements in plants. We used GRF to perform TIR/TDR, interspersed-repeat, and MITE detection in several species, including Arabidopsis (Arabidopsis thaliana), rice (Oryza sativa), and mouse (Mus musculus). As a generic bioinformatics tool in repeat finding implemented as a parallelized C++ program, GRF was faster and more sensitive than the existing inverted repeat/MITE detection tools based on numerical approaches (i.e. detectIR and detectMITE) in Arabidopsis and mouse. GRF is more sensitive than Inverted Repeat Finder in TIR detection, LTR_FINDER in short TDR detection (≤1,000 nt), and phRAIDER in interspersed repeat detection in Arabidopsis and rice. GRF is an open source available from Github.

Salamanders serve as important tetrapod models for developmental, regeneration and evolutionary studies. An extensive molecular toolkit makes the Mexican axolotl ( Ambystoma mexicanum ) a key representative salamander for molecular investigations. Here we report the sequencing and assembly of the 32-gigabase-pair axolotl genome using an approach that combined long-read sequencing, optical mapping and development of a new genome assembler (MARVEL). We observed a size expansion of introns and intergenic regions, largely attributable to multiplication of long terminal repeat retroelements. We provide evidence that intron size in developmental genes is under constraint and that species-restricted genes may contribute to limb regeneration. The axolotl genome assembly does not contain the essential developmental gene Pax3 . However, mutation of the axolotl Pax3 paralogue Pax7 resulted in an axolotl phenotype that was similar to those seen in Pax3 −/− and Pax7 −/− mutant mice. The axolotl genome provides a rich biological resource for developmental and evolutionary studies. Sequencing and assembly of the 32-Gb genome of the Mexican axolotl reveals that it lacks the developmental gene Pax3 , which is essential in other vertebrates; the genome sequence could improve our understanding of the evolution of the axolotl’s remarkable regenerative capabilities. Axolotl genome sequence Elly Tanaka, Eugene Myers and colleagues report the genome sequence of the axolotl, a model organism for developmental, regeneration and evolutionary studies. To sequence and assemble this large and complex genome, the authors used a combination of long- and short-read sequencing, optical mapping and a new genome assembly pipeline, MARVEL, optimized for long-read sequencing of complex genomes. The genome assembly shows an expansion of long terminal repeat retroelements and the presence of a large HoxA cluster, but also a reduction in the number of Pax-family genes in the genome of this popular salamander.

Chromatin architecture has been implicated in cell type-specific gene regulatory programs, yet how chromatin remodels during development remains to be fully elucidated. Here, by interrogating chromatin reorganization during human pluripotent stem cell (hPSC) differentiation, we discover a role for the primate-specific endogenous retrotransposon human endogenous retrovirus subfamily H (HERV-H) in creating topologically associating domains (TADs) in hPSCs. Deleting these HERV-H elements eliminates their corresponding TAD boundaries and reduces the transcription of upstream genes, while de novo insertion of HERV-H elements can introduce new TAD boundaries. The ability of HERV-H to create TAD boundaries depends on high transcription, as transcriptional repression of HERV-H elements prevents the formation of boundaries. This ability is not limited to hPSCs, as these actively transcribed HERV-H elements and their corresponding TAD boundaries also appear in pluripotent stem cells from other hominids but not in more distantly related species lacking HERV-H elements. Overall, our results provide direct evidence for retrotransposons in actively shaping cell type- and species-specific chromatin architecture. Genetic deletion or transcriptional silencing of HERV-H elements in human pluripotent stem cells (hPSCs) eliminates nearby topologically associating domain boundaries, while de novo insertion of HERV-H elements can introduce new ones. Mutations of specific HERV-H elements can impact hPSC differentiation.

The genomes of virtually all organisms contain repetitive sequences that are generated by the activity of transposable elements (transposons). Transposons are mobile genetic elements that can move from one genomic location to another; in this process, they amplify and increase their presence in genomes, sometimes to very high copy numbers. In this Review we discuss new evidence and ideas that the activity of retrotransposons, a major subgroup of transposons overall, influences and even promotes the process of ageing and age-related diseases in complex metazoan organisms, including humans. Retrotransposons have been coevolving with their host genomes since the dawn of life. This relationship has been largely competitive, and transposons have earned epithets such as ‘junk DNA’ and ‘molecular parasites’. Much of our knowledge of the evolution of retrotransposons reflects their activity in the germline and is evident from genome sequence data. Recent research has provided a wealth of information on the activity of retrotransposons in somatic tissues during an individual lifespan, the molecular mechanisms that underlie this activity, and the manner in which these processes intersect with our own physiology, health and well-being. This Review discusses how the activity of retrotransposons influences ageing and the role of these mobile genetic elements in age-related diseases and their treatment.

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.