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PubMed2025

A comprehensive atlas of full-length Arabidopsis eccDNA populations identifies their genomic origins and epigenetic regulation.

Extrachromosomal circular DNA (eccDNA) has been described in several eukaryotic species and has been shown to impact phenomena as diverse as cancer and herbicide tolerance. EccDNA is thought to arise mainly through transposable element (TE) mobilization. Because studies based on short-read sequencing cannot efficiently identify full-length eccDNA forms generated from TEs, we employed the CIDER-Seq pipeline based on long-read sequencing, to obtain full-length eccDNAs from Arabidopsis. The generated eccDNA datasets identified centromeric/pericentromeric regions as hotspots of eccDNAs with several eccDNA molecules originating from Helitron and LTR TEs. To investigate the role of epigenetic marks on TE-derived eccDNA biogenesis, we studied Arabidopsis methylation mutants dcl3, rdr6, ros1, and ddm1. Contrasting the TE-suppression previously reported in the hypermethylated ros1 mutants, we identified activation of TEs in ros1, specifically of LTR/Gypsy TEs. An enrichment of LTR/Copia elements was identified in actively dividing calli and the shoot apical meristem (SAM). Uncharacterized "variable TEs" with high eccDNA and expression were identified in the SAM, including ATCOPIA58. Together, our study reveals the genomic origins of eccDNAs and delineates the link between epigenetic regulation, transposon mobilization, and eccDNA biogenesis.

Arabidopsis↗

PubMed2026

Discovery and validation of GNA12circle as a first-trimester plasma eccDNA marker for early-onset preeclampsia.

BACKGROUND: Early-onset preeclampsia (EOPE) is a major cause of maternal and perinatal morbidity and is characterized by placental dysfunction, systemic endothelial injury, and hypertensive vascular stress. Because hypertensive disorders of pregnancy may also signal later maternal cardiovascular and cerebrovascular vulnerability, effective biomarkers for first-trimester risk assessment remain clinically important. Extrachromosomal circular DNA (eccDNA), a stable form of circulating cell-free DNA, has emerged as a potential source of disease-associated biomarkers. This study aimed to characterize first-trimester plasma eccDNA alterations associated with subsequent EOPE and to identify and validate a candidate circulating eccDNA marker for early risk assessment. METHODS: A two-stage nested case-control study was conducted within a prospective birth cohort. In the discovery stage, plasma samples collected at 11-13 weeks of gestation from 5 women who subsequently developed EOPE and 5 matched normotensive controls were profiled by Circle-Seq to characterize genome-wide eccDNA alterations. Candidate eccDNAs were prioritized through differential abundance analysis and were further confirmed by outward PCR and Sanger sequencing. In the validation stage, the candidate selected marker was quantified by junction-specific qPCR in an independent cohort of 109 EOPE cases and 109 controls. Its potential predictive value was further evaluated alone and in combination with routine first-trimester clinical variables. RESULTS: In the exploratory discovery analysis, 410 nominally differentially abundant candidate eccDNAs were identified as a hypothesis-generating pool. Among these, GNA12circle (chr7:2876332-2,876,692) was prioritized and experimentally validated at the circular junction. In the independent validation cohort, plasma GNA12circle levels were significantly higher in women who later developed EOPE than in controls. When combined with routine first-trimester variables, GNA12circle improved predictive performance. The RF model showed the best overall cross-validated performance among the evaluated classifiers, with a mean held-out test-fold AUC of 0.843. CONCLUSION: First-trimester plasma eccDNA profiling revealed distinct alterations associated with subsequent EOPE, from which GNA12circle was identified and validated as a candidate circulating marker. These findings support further investigation of circulating eccDNA for early EOPE risk assessment in larger multicenter populations.

Humans↗

PubMed2026

Circle-seq analysis reveals the involvement of eccDNAs in salt stress response of bermudagrass (Cynodon dactylon).

Extrachromosomal circular DNAs (eccDNAs) have been identified in a wide variety of plant species and play a pivotal role in genomic plasticity, emerging as key drivers of stress adaptation. However, the putative roles of eccDNAs under environmental stress remain largely unexplored in plants. As a high-quality turfgrass, bermudagrass (Cynodon dactylon L.) is a pivotal species for the reclamation and improvement of saline-alkali soils. Therefore, we performed a comprehensive analysis of the eccDNA profiles in bermudagrass under salt stress. A total of 1,068 eccDNAs were identified across all chromosomes. These eccDNAs were characterized by short lengths (ranging from 100 bp to 1 kb) and low GC content. Their genomic distribution was not entirely random but rather exhibited a certain preference for intergenic regions and coding sequences (CDS). Crucially, null model analysis of A/T-rich junction sites revealed that these eccDNAs primarily originate from physically unstable scaffold/matrix attachment regions (S/MARs) via stochastic fragmentation, followed by opportunistic circularization predominantly mediated by the non-homologous end joining (NHEJ) pathway. Notably, salt stress specifically enriched eccDNAs derived from DNA transposons, including the Tc1/Mariner, CACTA and MITE superfamilies. Overall, our findings reveal complex extrachromosomal structural dynamics in bermudagrass, offering novel insights into its genomic adaptation under environmental stress.

Cynodon↗

PubMed2006

Mouse major satellite DNA is prone to eccDNA formation via DNA Ligase IV-dependent pathway.

Elevated levels of extrachromosomal circular DNA (eccDNA or spcDNA) are closely associated with genomic instability and aging. Despite extensive studies, the mechanism of its generation in mammalian cells is unknown. We report here that mouse major satellite DNA (MSD) is prone to eccDNA formation and that the resulting molecules are multimeres of the basic repeat. Extrachromosomal circular major satellite (ECMS) DNA constitutes the majority of eccDNA in B16 mouse melanoma cells and is highly abundant in other mouse cells. Production of these molecules is enhanced in proliferating cells, suggesting that processes associated with DNA replication are involved in their appearance. Using siRNA technique we show that DNA Ligase IV is engaged in ECMS synthesis. Based on our findings we propose a novel two-step model for eccDNA formation in mammalian cells.

Animals↗

PubMed2003

Extrachromosomal circular DNA of tandemly repeated genomic sequences in Drosophila.

One characteristic of genomic plasticity is the presence of extrachromosomal circular DNA (eccDNA). This DNA is found in various eukaryotes from yeast to humans, and its levels are elevated by exposure to carcinogens. eccDNA is heterogeneous in size and composed of chromosomal sequences. In this study we used two-dimensional gel electrophoresis to detect and characterize eccDNA in Drosophila. We found eccDNA throughout the fly's life cycle. These molecules comprise up to 10% of the total repetitive DNA content, and their size ranges from <1 kb to >20 kb. The eccDNA population contains circular multimers of tandemly repeated genes such as histones, rDNA, Stellate, and the Suppressor of Stellate. Multimers of centromeric heterochromatin sequences are included in eccDNA as well. Our findings are consistent with the hypothesis that intramolecular homologous recombination between direct tandem repeats is a favorite mechanism for eccDNA formation. The level of eccDNA increased following MMS treatment of wild-type larvae, consistent with phenomena observed in cultured mammalian cells. This shows mutagen-induced eccDNA formation in the context of the whole organism for the first time. Mutations in the genes okra, mus309, and mei41 did not affect eccDNA under normal conditions or following mutagen treatment, implying that eccDNA formation is different from known pathways of DNA repair.

Animals↗

PubMed1994

Formation of extrachromosomal circular DNA in HeLa cells by nonhomologous recombination.

Extrachromosomal circular DNA (eccDNA) generated from chromosomal DNA is found in all mammalian cells and increases with cell stress or aging. Studies of eccDNA structure and mode of formation provide insight into mechanisms of instability of the mammalian genome. Previous studies have suggested that eccDNA is generated through a process involving recombination between repetitive sequences. However, we observed that approximately one half of the small eccDNA fragments cloned from HeLa S3 cells were composed entirely of nonrepetitive or low-copy DNA sequences. We analyzed four of these fragments by polymerase chain reaction and nucleotide sequencing and found that they were complete eccDNAs. We then screened a human genomic library with the eccDNAs to isolate the complementary chromosomal sequences. Comparing the recombination junctions within the eccDNAs with the chromosomal sequences from which they were derived revealed that nonhomologous recombination was involved in their formation. One of the eccDNAs was composed of two separate sequences from different parts of the genome. These results suggest that rejoining of ends of fragmented DNA is responsible for the generation of a substantial portion of the eccDNAs found in HeLa S3 cells.

Base Sequence↗

PubMed2025

eccDNABase: A Comprehensive and High-Quality Database for Extrachromosomal Circular DNA.

Extrachromosomal circular DNA (eccDNA) refers to small, circular DNA molecules that originate from chromosomal sequences and are prevalent across nearly all eukaryotic organisms. In humans, eccDNAs are widely distributed in normal tissues, cancerous tissues, and body fluids, where they play important roles in tumorigenesis and are often associated with poor clinical outcomes. Given their biological and clinical significance, a well-integrated and high-quality database is essential for advancing eccDNA-related research. To address this need, we developed eccDNABase, a comprehensive and curated resource for browsing, searching, and analyzing eccDNAs across multiple species. The database systematically catalogs eccDNA-disease associations from diverse tissues and organisms. Currently, eccDNABase contains 1,875,452 eccDNA-disease associations, encompassing 8,398 ecDNA entries across nine species, 63 diseases, and healthy individuals. Each entry provides detailed information, including eccDNA ID, type, chromosomal localization, species, tissue or cell line source, disease name and Disease Ontology ID, overlap length and percentage with genes, oncogene overlap, detection method, and links to literature and source databases. Given its extensive and curated datasets, eccDNABase serves as a valuable resource for both basic and translational research, offering deeper insights into the role of eccDNA in health and disease. The database is publicly accessible at http://cgga.org.cn/eccDNABase/.

Humans↗

PubMedDate not supplied

Extrachromosomal circular DNAs and genomic sequence plasticity in eukaryotic cells.

The ability of eukaryotic organisms of the same genotype to vary in developmental pattern or in phenotype according to varying environmental conditions is frequently associated with changes in extrachromosomal circular DNA (eccDNA) sequences. Although variable in size, sequence complexity, and copy number, the best characterized of these eccDNAs contain sequences homologous to chromosomal DNA which indicates that they might arise from genetic rearrangements, such as homologous recombination. The abundance of repetitive sequence families in eccDNAs is consistent with the notion that tandem repeats and dispersed repetitive elements participate in intrachromosomal recombination events. There is also evidence that a fraction of this DNA has characteristics similar to retrotransposons. It has been suggested that eccDNAs could reflect altered patterns of gene expression or an instability of chromosomal sequences during development and aging. This article reviews some of the findings and concepts regarding eccDNAs and sequence plasticity in eukaryotic genomes.

Animals↗

PubMed2001

A novel cell-free system reveals a mechanism of circular DNA formation from tandem repeats.

One characteristic of genomic plasticity is the presence of extrachromosomal circular DNA (eccDNA). High levels of eccDNA are associated with genomic instability, exposure to carcinogens and aging. We have recently reported developmentally regulated formation of eccDNA that occurs preferentially in pre-blastula Xenopus laevis embryos. Multimers of tandemly repeated sequences were over-represented in the circle population while dispersed sequences were not detected, indicating that circles were not formed at random from any chromosomal sequence. Here we present detailed mechanistic studies of eccDNA formation in a cell-free system derived from Xenopus egg extracts. We show that naked chromosomal DNA from sperm or somatic tissues serves as a substrate for direct tandem repeat circle formation. Moreover, a recombinant bacterial tandem repeat can generate eccDNA in the extract through a de novo mechanism which is independent of DNA replication. These data suggest that the presence of a high level of any direct tandem repeat can confer on DNA the ability to be converted into circular multimers in the early embryo irrespective of its sequence and that homologous recombination is involved in this process.

Animals↗

PubMed1990

Tissue-specific and age-related variations in repetitive sequences of mouse extrachromosomal circular DNAs.

Extrachromosomal circular (ecc) DNA was isolated from mouse brain, liver, and heart tissues at different ages. To determine the abundance of repetitive sequences in eccDNAs, preparations were probed for short-interspersed (B1 and B2), long-interspersed (L1), endogenous retroviral-like (IAP), and tandemly repeated satellite sequences (SAT) of the mouse genome. Together these sequence families comprise approximately 15% of the mouse genome. The hybridization results showed that each tissue had a characteristic pattern of repetitive sequence elements in eccDNAs, and the abundance of repetitive sequences changed as a function of age. Repetitive sequences decreased in liver and brain eccDNAs from 1 month to 8 months of age but appeared to remain stable thereafter. In contrast, repetitive sequence families in heart eccDNAs were constant from 1 month to 16 months of age but declined in 24-month-old mice. The present studies indicate that extrachromosomal sequences exhibit greater flexibility than chromosomal sequences.

Aging↗

PubMed2002

Formation of extrachromosomal circles from telomeric DNA in Xenopus laevis.

Instability and plasticity of telomeric DNA, which includes extrachromosomal DNA, are usually correlated with the absence of telomerase and with abnormal growth of mammalian cells. Here, we show the formation of extrachromosomal circular DNA of telomeric repeats (tel-eccDNA) during the development of Xenopus laevis. Tel-eccDNA is double-stranded relaxed circles composed of the vertebrate consensus telomeric repeats [TTAGGG](n). Its size varies from <2 to >20 kb and it comprises up to 10% of the total cellular telomere content of the early embryo (pre-MBT stage). The amount of tel-eccDNA is reduced in later developmental stages and in adult tissues. Using a cell-free system derived from Xenopus egg extracts, we show that tel-eccDNA can be formed de novo from the telomere chromosomal tracts of sperm nuclei and naked DNA in a replication-independent manner. These results reveal an unusual plasticity of telomeric DNA during normal development of Xenopus.

Animals↗

PubMed2005

Evidence for rolling circle replication of tandem genes in Drosophila.

Extrachromosomal circular DNA (eccDNA) is one characteristic of the plasticity of the eukaryotic genome. It is found in various organisms and contains sequences derived primarily from repetitive chromosomal DNA. Using 2D gel electrophoresis, we have previously detected eccDNA composed of chromosomal tandem repeats throughout the life cycle of Drosophila. Here, we report for the first time evidence suggesting the occurrence of rolling circle replication of eccDNA in Drosophila. We show, on 2D gels, specific structures that can be enriched by benzoylated naphthoylated DEAE-cellulose chromatography and were identified in other systems as rolling circle intermediates (RCIs). These RCIs are homologous to histone genes, Stellate and Suppressor of Stellate, which are all organized in the chromosomes as tandem repeats. RCIs are detected throughout the life cycle of Drosophila and in cultured fly cells. These structures are found regardless of the expression of the replicated gene or of its chromosomal copy number.

Animals↗

PubMed1990

Purification of eucaryotic extrachromosomal circular DNAs using exonuclease III.

A method for the isolation of eucaryotic extrachromosomal circular (ecc) DNA is described. Exonuclease III was used to preparatively digest linear and open circular forms of DNA; the resultant exonuclease-resistant molecules were then characterized by buoyant density gradient sedimentation and were found to be essentially covalently closed circular DNA. The efficiency of the exonuclease method was compared to ultracentrifugation techniques and was found to give yields greater than those obtained by two or more equilibrium density gradients. The utility of the exonuclease III technique was determined by purifying eccDNAs from mouse liver, brain, heart, and kidney tissues. The results showed that there are tissue-related differences in eccDNA content.

Animals↗

PubMed1987

Dispersed repetitive sequences of the mouse genome are differentially represented in extrachromosomal circular DNAs in vivo.

Eukaryotic cells contain extrachromosomal circular (ecc) DNAs which are homologous to chromosomal sequences. We have isolated eccDNAs from whole tissues of C57BL/6 mice. Using hybridization techniques, we show that R-, MIF-, B1-, and B2-dispersed repetitive sequences of the mouse genome are differentially represented in heart, brain, and liver tissues. Moreover, we show that the relative abundance of B2 sequences in heart and liver eccDNAs is higher than the relative abundance of the other repetitive sequence families studied.

Animals↗

PubMed1998

DNA-mediated transport of the intermediate filament protein vimentin into the nucleus of cultured cells.

A number of characteristic properties of intermediate filament (IF) proteins, such as nucleic acid-binding activity, affinity for histones and structural relatedness to transcription factors and nuclear matrix proteins, in conjunction with the tight association of IFs with the nucleus, suggest that these proteins might also fulfill nuclear functions in addition to their structure-organizing and -stabilizing activities in the cytoplasm. Yet, cytoplasmic IF proteins do not possess nuclear localization signals. In a search for carriers capable of transporting the IF protein vimentin into the nucleus, complexes of FITC-vimentin with various DNAs were microinjected into the cytoplasm of cultured cells and the intracellular distribution of the protein was followed by confocal laser scanning microscopy. The single-stranded oligodeoxyribonucleotides oligo(dG)25, oligo[d(GT)12G] and oligo[d(G3T2A)4G] proved to be excellent nuclear carriers for vimentin. However, in fibroblasts, fluorescence-labeled vimentin taken up by the nuclei remained undetectable with affinity-purified, polyclonal anti-vimentin antibody, whereas it was readily identifiable in the nuclei of microinjected epithelial cells in this way. Moreover, when FITC-vimentin was preinjected into fibroblasts and allowed to assemble into the endogenous vimentin filament system, it was still transferred into the nucleus by post-injected oligo(dG)25, although to a lesser extent. Superhelical circular DNAs, like pBR322, SV40 and mitochondrial DNA, were also characterized by considerable capacities for nuclear vimentin transport; these transport potentials were totally destroyed by relaxation or linearization of the DNA molecules. Nevertheless, certain linear double-stranded DNA molecules with a high affinity for vimentin IFs, such as repetitive telomere and centromere or mobile long interspersed repeat (LINE) DNA, could carry FITC-vimentin into the nucleus. This was also true for a 375 bp extrachromosomal linear DNA fragment which occurs in the cytoplasm of mouse tumor cells and which is capable of immortalizing human lymphocytes. On the basis of these results, it appears very likely that cellular and viral products of reverse transcription as well as other extrachromosomal DNAs, which are circular, superhelical and apparently shuttling between the cytoplasm and the nucleus (eccDNA), are constantly loaded with vimentin in vimentin-positive cells. Since such DNAs are considered as markers of genomic instability, it is conceivable that vimentin directly participates as an architectural, chromatin-modifying protein in recombinatorial processes set off by these DNAs in the nucleus.

Animals↗