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Møller, Henrik D., Lance Parsons, Tue S. Jørgensen, David Botstein i Birgitte Regenberg. "Extrachromosomal circular DNA is common in yeast". Proceedings of the National Academy of Sciences 112, nr 24 (2.06.2015): E3114—E3122. http://dx.doi.org/10.1073/pnas.1508825112.
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Examples of extrachromosomal circular DNAs (eccDNAs) are found in many organisms, but their impact on genetic variation at the genome scale has not been investigated. We mapped 1,756 eccDNAs in the Saccharomyces cerevisiae genome using Circle-Seq, a highly sensitive eccDNA purification method. Yeast eccDNAs ranged from an arbitrary lower limit of 1 kb up to 38 kb and covered 23% of the genome, representing thousands of genes. EccDNA arose both from genomic regions with repetitive sequences ≥15 bases long and from regions with short or no repetitive sequences. Some eccDNAs were identified in several yeast populations. These eccDNAs contained ribosomal genes, transposon remnants, and tandemly repeated genes (HXT6/7, ENA1/2/5, and CUP1-1/-2) that were generally enriched on eccDNAs. EccDNAs seemed to be replicated and 80% contained consensus sequences for autonomous replication origins that could explain their maintenance. Our data suggest that eccDNAs are common in S. cerevisiae, where they might contribute substantially to genetic variation and evolution.
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Zuo, Shanru, Xueguang Li, Yide Yang, Junhua Zhou i Quanyuan He. "A Quick Method to Synthesize Extrachromosomal Circular DNA In Vitro". Molecules 28, nr 10 (22.05.2023): 4236. http://dx.doi.org/10.3390/molecules28104236.
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Extrachromosomal circular DNA (eccDNA) is a special class of circular DNA in eukaryotes. Recent studies have suggested that eccDNA is the product of genomic instability and has important biological functions to regulate many downstream biological processes. While NGS (Next-Generation Sequencing)-based eccDNA sequencing has led to the identification of many eccDNAs in both healthy and diseased tissues, the specific biological functions of individual eccDNAs have yet to be clearly elucidated. Synthesizing eccDNAs longer than 1 kb with specific sequences remains a major challenge in the field, which has hindered our ability to fully understand their functions. Current methods for synthesizing eccDNAs primarily rely on chemical oligo synthesis, ligation, or the use of a specific gene editing and recombination systems. Therefore, these methods are often limited by the length of eccDNAs and are complex, expensive, as well as time-consuming. In this study, we introduce a novel method named QuickLAMA (Ligase-Assisted Minicircle Accumulation) for rapidly synthesizing eccDNAs up to 2.6 kb using a simple PCR and ligation approach. To validate the efficacy of our method, we synthesized three eccDNAs of varying lengths from cancer tissue and PC3 cells and confirmed successful circularization through sequencing and restriction enzyme digestion. Additional analyses have demonstrated that this method is highly efficient, cost-effective, and time-efficient, with good reproducibility. Using the method, a well-trained molecular biologist can synthesize and purify multiple eccDNAs within a single day, and it can be easily standardized and processed in a high-throughput manner, indicating the potential of the method to produce a wide range of desired eccDNAs and promote the translation of eccDNA research into clinical applications.
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Merkulov, Pavel, Ekaterina Egorova i Ilya Kirov. "Composition and Structure of Arabidopsis thaliana Extrachromosomal Circular DNAs Revealed by Nanopore Sequencing". Plants 12, nr 11 (30.05.2023): 2178. http://dx.doi.org/10.3390/plants12112178.
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Extrachromosomal circular DNAs (eccDNAs) are enigmatic DNA molecules that have been detected in a range of organisms. In plants, eccDNAs have various genomic origins and may be derived from transposable elements. The structures of individual eccDNA molecules and their dynamics in response to stress are poorly understood. In this study, we showed that nanopore sequencing is a useful tool for the detection and structural analysis of eccDNA molecules. Applying nanopore sequencing to the eccDNA molecules of epigenetically stressed Arabidopsis plants grown under various stress treatments (heat, abscisic acid, and flagellin), we showed that TE-derived eccDNA quantity and structure vary dramatically between individual TEs. Epigenetic stress alone did not cause eccDNA up-regulation, whereas its combination with heat stress triggered the generation of full-length and various truncated eccDNAs of the ONSEN element. We showed that the ratio between full-length and truncated eccDNAs is TE- and condition-dependent. Our work paves the way for further elucidation of the structural features of eccDNAs and their connections with various biological processes, such as eccDNA transcription and eccDNA-mediated TE silencing.
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Petito, V., F. DI VINCENZO, D. Gerovska, A. Piazzesi, A. Russo, L. Turchini, L. Masi i in. "P096 Human extrachromosomal circular DNA is an emerging biomarker in Inflammatory Bowel Disease". Journal of Crohn's and Colitis 18, Supplement_1 (1.01.2024): i375. http://dx.doi.org/10.1093/ecco-jcc/jjad212.0226.
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Abstract Background Inflammatory Bowel Diseases (IBD) are chronic multifactorial disorders, which affect the gastrointestinal tract, including Ulcerative Colitis (UC) and Crohn’s Disease (CD). The existence of extrachromosomal circular DNA fragments (eccDNA) is well established, and it arises from all parts of the genome. eccDNA has mainly been studied in the context of cancer and not in relation to other diseases, and it has become a promising diagnostic and prognostic biomarker for different types of cancer. Herein, we investigate for the first time the role of eccDNA in IBD. Methods Forty consecutive IBD patients (19 CD, 21 UC) and 13 HC were enrolled, who underwent screening colonoscopy were prospectively enrolled at our center in this observational, case-controlled study. In IBD patients, disease activity was assessed using PMS and MES for UC, and HBI and SES-CD for CD. Colonic biopsies were collected from both inflamed and healthy mucosa in IBD patients and from HC. eccDNA was enriched, sequenced, and identified with Circle Finder from intestinal biopsies. Results Colonic mucosal samples from IBD patients showed increased average of eccDNAs, across all chromosomes than samples from HC. Furthermore, there was a slight yet significant tendency for larger eccDNAs in IBDs compared to HCs. Focusing on eccDNA coming from genic elements ("genic eccDNAs"), approximately 60% were fragments from protein coding genes, 32% from non-coding RNAs and 8% from pseudogenes. IBD patients had, on average, significantly more genic eccDNAs in their intestines as compared to HC. Moreover, IBD in remission had fewer eccDNAs in their intestines than active disease, although not statistically significant. eccDNAs from phosphodiesterase genes and genes involved in lipid metabolism were enriched in patients with active IBD than patients in remission. eccDNA from inflamed mucosa (both in UC and in CD) show an enrichment of genes related to inflammatory and immune pathways, such as MAPK, mTOR, ErB, Rap-1 and cGMP (SPOKE3, GRID2, DLEU1, ITGA8, NRG1). Conclusion We are the first to uncover an IBD-specific pattern of eccDNA production. Furthermore, we identified genic hotspots which characterize active vs. inactive disease and inflamed vs. healthy colonic tissue. We propose that eccDNA identification could be a promising new diagnostic marker for IBD patients.
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Ye, Jianyu, Peixin Huang, Kewei Ma, Zixin Zhao, Ting Hua, Wenjing Zai, Jieliang Chen i Xiutao Fu. "Genome-Wide Extrachromosomal Circular DNA Profiling of Paired Hepatocellular Carcinoma and Adjacent Liver Tissues". Cancers 15, nr 22 (7.11.2023): 5309. http://dx.doi.org/10.3390/cancers15225309.
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Hepatocellular carcinoma (HCC) develops through multiple mechanisms. While recent studies have shown the presence of extrachromosomal circular DNA (eccDNA) in most cancer types, the eccDNA expression pattern and its association with HCC remain obscure. We aimed to investigate this problem. The genome-wide eccDNA profiles of eight paired HCC and adjacent non-tumor tissue samples were comprehensively elucidated based on Circle-seq, and they were further cross-analyzed with the RNA sequencing data to determine the association between eccDNA expression and transcriptome dysregulation. A total of 60,423 unique eccDNA types were identified. Most of the detected eccDNAs were smaller than 1 kb, with a length up to 182,363 bp and a mean sizes of 674 bp (non-tumor) and 813 bp (tumor), showing a greater association with gene-rich rather than with gene-poor regions. Although there was no statistical difference in length and chromosome distribution, the eccDNA patterns between HCC and adjacent non-tumor tissues showed significant differences at both the chromosomal and single gene levels. Five of the eight HCC tissues showed significantly higher amounts of chromosome 22-derived eccDNA expression compared to the non-tumor tissue. Furthermore, two genes, SLC16A3 and BAIAP2L2, with a higher transcription level in tumor tissues, were related to eccDNAs exclusively detected in three HCC samples and were negatively associated with survival rates in HCC cohorts from public databases. These results indicate the existence and massive heterogeneity of eccDNAs in HCC and adjacent liver tissues, and suggest their potential association with dysregulated gene expression.
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Di Vincenzo, F., V. Petito, D. Gerovska, A. Piazzesi, A. Russo, L. Turchini, L. Masi i in. "P0032 Human Extrachromosomal Circular DNA (EccDNA) is a Novel Biomarker in Inflammatory Bowel Disease". Journal of Crohn's and Colitis 19, Supplement_1 (styczeń 2025): i377. https://doi.org/10.1093/ecco-jcc/jjae190.0206.
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Abstract Background Inflammatory Bowel Diseases (IBD), comprising Ulcerative Colitis (UC) and Crohn’s Disease (CD), are chronic, relapsing-remitting disorders of the gastrointestinal tract with unclear etiology. Identifying reliable biomarkers for predicting disease progression and treatment response remains a priority. Extrachromosomal circular DNA (eccDNA) has shown promise as a diagnostic and prognostic biomarker in oncology, but its potential in IBD patients, including the gene fragments involved, has not been extensively studied. Methods This monocentric, observational case-control study enrolled IBD patients and healthy controls (HC) undergoing colonoscopy for colorectal cancer screening at our center. IBD disease activity was assessed using the Partial Mayo Score and Mayo Endoscopic Subscore (MES) for UC, and the Harvey-Bradshaw Index and Simple Endoscopic Score (SES-CD) for CD. Colonic biopsies were collected from both inflamed and healthy mucosa of IBD patients, and from HCs. eccDNA was purified using the Circle-Seq method; detection was performed with the Circle Finder pipeline. The study analyzed differences in eccDNA abundances between IBD patients and HCs, focusing on Differentially Produced per Gene eccDNAs (DPpGCs). Results In total, 93 IBD patients (38 CD, 39 UC) and 16 HC were included. IBD patients showed a significantly higher abundance of eccDNAs compared to HC, with this increase observed across all chromosomes, suggesting a global upregulation of eccDNA production throughout the human genome. There was also a statistically significant trend towards larger eccDNA fragments in IBD biopsies. Notably, even when considering only eccDNA derived from genic elements ("genic eccDNAs") IBD patients exhibited a significantly higher abundance of eccDNA compared to HCs. Analysis of DPpGCs (fold change >1 log2, p < 0.01) identified 152 genes enriched in IBD, including GRID2 and NRG1. In CD patients, 70 genes, such as FGF14, SOX5, and ZBTB20, were enriched, while UC patients had 123 enriched genes, including NRG1, SPOCK3, and ATP13A4. Patients in endoscopic remission (SES-CD< 3, MES 0-1) exhibited fewer eccDNAs, though this reduction was not statistically significant. Among identified DPpGCs, key genes included FARS2, HERC3, and PNK2. When analyzing UC and CD seperately, we found a statistically significant increase of eccDNA production in active UC, but not in CD, with NRG1 being notably overrepresented, suggesting its potential as a UC-specific biomarker. Conclusion Our study unveils a unique pattern of eccDNA production in IBD. We showed that circles harboring specific genes can distinguish UC and CD from HCs with statistical significance (p<0.01), indicating that eccDNA profiling may represent a novel diagnostic tool for IBD patients.
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Sin, Sarah T. K., Peiyong Jiang, Jiaen Deng, Lu Ji, Suk Hang Cheng, Anindya Dutta, Tak Y. Leung, K. C. Allen Chan, Rossa W. K. Chiu i Y. M. Dennis Lo. "Identification and characterization of extrachromosomal circular DNA in maternal plasma". Proceedings of the National Academy of Sciences 117, nr 3 (3.01.2020): 1658–65. http://dx.doi.org/10.1073/pnas.1914949117.
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We explored the presence of extrachromosomal circular DNA (eccDNA) in the plasma of pregnant women. Through sequencing following either restriction enzyme or Tn5 transposase treatment, we identified eccDNA molecules in the plasma of pregnant women. These eccDNA molecules showed bimodal size distributions peaking at ∼202 and ∼338 bp with distinct 10-bp periodicity observed throughout the size ranges within both peaks, suggestive of their nucleosomal origin. Also, the predominance of the 338-bp peak of eccDNA indicated that eccDNA had a larger size distribution than linear DNA in human plasma. Moreover, eccDNA of fetal origin were shorter than the maternal eccDNA. Genomic annotation of the overall population of eccDNA molecules revealed a preference of these molecules to be generated from 5′-untranslated regions (5′-UTRs), exonic regions, and CpG island regions. Two sets of trinucleotide repeat motifs flanking the junctional sites of eccDNA supported multiple possible models for eccDNA generation. This work highlights the topologic analysis of plasma DNA, which is an emerging direction for circulating nucleic acid research and applications.
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Khan, Safir Ullah, i Munir Ullah Khan. "Extra Chromosomal Circular DNA: Recent Advances in Research". Journal of Biomedical Research & Environmental Sciences 3, nr 4 (kwiecień 2022): 445–52. http://dx.doi.org/10.37871/jbres1463.
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Extrachromosomal circular DNA (eccDNA) is a circular DNA molecule outside of eukaryotic staining, in which DNA forms in the genome or exogenous DNA in the cell. eccDNA is a special class of genetic material that can carry complete genes encoding functional proteins or RNA. Studies have shown that eccDNA can participate in various physiological and pathological processes in a special way, such as aging and the occurrence of tumors. This paper reviews the latest research progress of eccDNA and further expounds on the relationship between eccDNA and tumors.
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Deng, Enze, i Xiaoying Fan. "Categorizing Extrachromosomal Circular DNA as Biomarkers in Serum of Cancer". Biomolecules 14, nr 4 (17.04.2024): 488. http://dx.doi.org/10.3390/biom14040488.
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Extrachromosomal circular DNA (eccDNA), a double-stranded circular DNA molecule found in multiple organisms, has garnered an increasing amount of attention in recent years due to its close association with the initiation, malignant progression, and heterogeneous evolution of cancer. The presence of eccDNA in serum assists in non-invasive tumor diagnosis as a biomarker that can be assessed via liquid biopsies. Furthermore, the specific expression patterns of eccDNA provide new insights into personalized cancer therapy. EccDNA plays a pivotal role in tumorigenesis, development, diagnosis, and treatment. In this review, we comprehensively outline the research trajectory of eccDNA, discuss its role as a diagnostic and prognostic biomarker, and elucidate its regulatory mechanisms in cancer. In particular, we emphasize the potential application value of eccDNA in cancer diagnosis and treatment and anticipate the development of novel tumor diagnosis strategies based on serum eccDNA in the future.
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Diaz-Lara, Alfredo, David H. Gent i Robert R. Martin. "Identification of Extrachromosomal Circular DNA in Hop via Rolling Circle Amplification". Cytogenetic and Genome Research 148, nr 2-3 (2016): 237–40. http://dx.doi.org/10.1159/000445849.
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During a survey for new viruses affecting hop plants, a circular DNA molecule was identified via rolling circle amplification (RCA) and later characterized. A small region of the 5.7-kb long molecule aligned with a microsatellite region in the Humulus lupulus genome, and no coding sequence was identified. Sequence analysis and literature review suggest that the small DNA molecule is an extranuclear DNA element, specifically, an extrachromosomal circular DNA (eccDNA), and its presence was confirmed by electron microscopy. This work is the first report of eccDNAs in the family Cannabaceae. Additionally, this work highlights the advantages of using RCA to study extrachromosomal DNA in higher plants.
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Tong, Xinyu, Chao Lei, Yilin Liu, Mei Yin, Huan Peng, Qunnan Qiu, Yongjie Feng, Xiaolong Hu, Chengliang Gong i Min Zhu. "Genome-Wide Characterization of Extrachromosomal Circular DNA in the Midgut of BmCPV-Infected Silkworms and Its Potential Role in Antiviral Responses". International Journal of Molecular Sciences 26, nr 2 (19.01.2025): 818. https://doi.org/10.3390/ijms26020818.
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Extrachromosomal circular DNAs (eccDNAs) has been found to be widespread and functional in various organisms. However, comparative analyses of pre- and post-infection of virus are rarely known. Herein, we investigated the changes in expression patterns of eccDNA following infection with Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) and explore the role of eccDNA in viral infection. Circle-seq was used to analyze eccDNAs in the midgut of BmCPV-infected and BmCPV-uninfected silkworms. A total of 5508 eccDNAs were identified, with sizes varying from 72 bp to 17 kb. Most of eccDNAs are between 100 to 1000 bp in size. EccDNA abundance in BmCPV-infected silkworms was significantly higher than in BmCPV-uninfected silkworms. GO and KEGG analysis of genes carried by eccDNAs reveals that most are involved in microtubule motor activity, phosphatidic acid binding, cAMP signaling pathway, and pancreatic secretion signaling pathways. Several eccDNAs contain sequences of the transcription factor SOX6, sem-2, sp8b, or Foxa2. Association analysis of eccDNA-mRNA/miRNA/circRNA revealed that some highly expressed genes are transcribed from relevant sequences of eccDNA and the transcription of protein coding genes influenced the frequency of eccDNA. BmCPV infection resulted in changes in the expression levels of six miRNAs, but no known miRNAs with altered expression levels due to changes in eccDNA abundance were identified. Moreover, it was found that 1287 and 924 sequences representing back-spliced junctions of circRNAs were shared by the junctions of eccDNAs in the BmCPV-infected and uninfected silkworms, respectively, and some eccDNAs loci were shared by circRNAs on Chromosomes 2, 7, 11, 14, and 24, suggesting some eccDNAs may exert its function by being transcribed into circRNAs. These findings suggest that BmCPV infection alter the expression pattern of eccDNAs, leading to changes in RNA transcription levels, which may play roles in regulating BmCPV replication. In the future, further experiments are needed to verify the association between eccDNA-mRNA/miRNA/circRNA and its function in BmCPV infection.
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Møller, Henrik Devitt, Jazmín Ramos-Madrigal, Iñigo Prada-Luengo, M. Thomas P. Gilbert i Birgitte Regenberg. "Near-Random Distribution of Chromosome-Derived Circular DNA in the Condensed Genome of Pigeons and the Larger, More Repeat-Rich Human Genome". Genome Biology and Evolution 12, nr 2 (27.12.2019): 3762–77. http://dx.doi.org/10.1093/gbe/evz281.
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Abstract Extrachromosomal circular DNA (eccDNA) elements of chromosomal origin are known to be common in a number of eukaryotic species. However, it remains to be addressed whether genomic features such as genome size, the load of repetitive elements within a genome, and/or animal physiology affect the number of eccDNAs. Here, we investigate the distribution and numbers of eccDNAs in a condensed and less repeat-rich genome compared with the human genome, using Columba livia domestica (domestic rock pigeon) as a model organism. By sequencing eccDNA in blood and breast muscle from three pigeon breeds at various ages and with different flight behavior, we characterize 30,000 unique eccDNAs. We identify genomic regions that are likely hotspots for DNA circularization in breast muscle, including genes involved in muscle development. We find that although eccDNA counts do not correlate with the biological age in pigeons, the number of unique eccDNAs in a nonflying breed (king pigeons) is significantly higher (9-fold) than homing pigeons. Furthermore, a comparison between eccDNA from skeletal muscle in pigeons and humans reveals ∼9-10 times more unique eccDNAs per human nucleus. The fraction of eccDNA sequences, derived from repetitive elements, exist in proportions to genome content, that is, human 72.4% (expected 52.5%) and pigeon 8.7% (expected 5.5%). Overall, our results support that eccDNAs are common in pigeons, that the amount of unique eccDNA types per nucleus can differ between species as well as subspecies, and suggest that eccDNAs from repeats are found in proportions relative to the content of repetitive elements in a genome.
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Yerlici, V. Talya, Michael W. Lu, Carla R. Hoge, Richard V. Miller, Rafik Neme, Jaspreet S. Khurana, John R. Bracht i Laura F. Landweber. "Programmed genome rearrangements in Oxytricha produce transcriptionally active extrachromosomal circular DNA". Nucleic Acids Research 47, nr 18 (28.08.2019): 9741–60. http://dx.doi.org/10.1093/nar/gkz725.
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Abstract Extrachromosomal circular DNA (eccDNA) is both a driver of eukaryotic genome instability and a product of programmed genome rearrangements, but its extent had not been surveyed in Oxytricha, a ciliate with elaborate DNA elimination and translocation during development. Here, we captured rearrangement-specific circular DNA molecules across the genome to gain insight into its processes of programmed genome rearrangement. We recovered thousands of circularly excised Tc1/mariner-type transposable elements and high confidence non-repetitive germline-limited loci. We verified their bona fide circular topology using circular DNA deep-sequencing, 2D gel electrophoresis and inverse polymerase chain reaction. In contrast to the precise circular excision of transposable elements, we report widespread heterogeneity in the circular excision of non-repetitive germline-limited loci. We also demonstrate that circular DNAs are transcribed in Oxytricha, producing rearrangement-specific long non-coding RNAs. The programmed formation of thousands of eccDNA molecules makes Oxytricha a model system for studying nucleic acid topology. It also suggests involvement of eccDNA in programmed genome rearrangement.
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Wu, Zijuan, Wei Zhang, Luqiao Wang, Lei Fan, Jianyong Li i Hui Jin. "Extrachromosomal Circular DNA Drives the Progression of DLBCL through Activating the Sting Pathway". Blood 142, Supplement 1 (28.11.2023): 1628. http://dx.doi.org/10.1182/blood-2023-190771.
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Objective Chromosome instability (CIN) as a hallmark of cancer is correlated with the prognosis of patients with diffuse large B cell lymphoma (DLBCL). However, little is known about how it drives the tumorigenesis and progression. DNA damage affects CIN and accumulated cytosolic DNA which activates the DNA sensing machinery cGAS-STING pathway in a sequence-independent manner. Extrachromosomal circular DNA (eccDNA), a type of circular DNA that derived from genomic DNA is independent of chromosomes. Existing widely in nature, eccDNA could be involved in tumorigenesis, heterogeneity and drug resistance. The purpose of this study is to reveal the expression profile of eccDNA in DLBCL, and to explore how eccDNA promotes the occurrence and development of the disease through the cGAS-independent STING pathway. Methods The expression profile of eccDNA in DLBCL was detected through multi-omics sequencing analysis including circular DNA sequencing (circle-seq), single-cell sequencing (scRNA-seq), whole exome sequencing (WES) and atomic force microscopy. CCK8, scRNA-seq, etc. were used to reveal the activation of eccDNA on the STING pathway to promote cell proliferation. In vivo and in vitro models were treated with chemotherapeutic drugs to verify the hypothesis that DNA damage induces the production of eccDNA, thereby activating the cGAS-independent STING pathway. GEO databases were applied to verify the prognosis of eccDNA-related gene sets, animal models to explore the anti-tumor effect of DNA damage therapy combined with STING inhibitors. Results Through the integration of multi-omics analysis results of 18 DLBCL cell lines, we divided DLBCL cells into two groups with high (H group) or low (L group) eccDNA abundance separately and confirmed that cells with high wGII were accompanied by abundant eccDNA. It suggested the potential roles of eccDNA in prognostic evaluation. Subsequent research revealed that eccDNA was upregulated in patients with DLBCL especially in R/R DLBCL. Pseudo-time analysis indicated that cells developed in two different differentiation directions. GSEA analysis demonstrated that high abundance of eccDNA contributed to the cell proliferative potential. To verify the role of eccDNA in cell proliferation, eccDNA extracted from H group cells were transfected into L group cells. As a result, cells transfected with eccDNA showed a significantly higher rate of propagation. These results confirmed that eccDNA had the promotional effects on proliferation DLBCL cells. GEO databases (GSE31312, GSE10846 and GSE87371) were applied to verify the prognosis of eccDNA-related gene sets. Gens that upregulated in H group was selected to construct a panel and overall survival analysis showed that patients with high levels of the panel had a worse prognosis. DNA damage repair mechanism is a key component to maintain the stability of genome. Numerous studies have suggested that DNA damage repair is conducive to the generation of eccDNA. Here, we found that cells with serious DNA damage degree were accompanied with increased γH2AX levels. EccDNA was induced with the treatment of DNA damage agents (cisplatin, doxorubicin, irinotecan and olaparib). Meanwhile, the levels of p-STING and downstream proteins were significantly upregulated. This phenomenon was also confirmed with immunodeficient and immunocompetent mice. H-151, the inhibitor of STING showed effective inhibitory effect on DLBCL through in vitro and in vivo assay. cells with high eccDNA abundance, and the results were further confirmed with scRNA-seq analysis. The combinational effects of STING inhibitor with DNA damage agents were observed. These results suggested that cells with high eccDNA abundance were more sensitive to the inhibition of STING pathway and the combined use of chemotherapy drugs and STING inhibitors can significantly enhance the anti-tumor effect. Conclusion DLBCL is a highly heterogeneous aggressive non-Hodgkin's lymphoma. STING plays a double-edged role in tumor development and immune regulation. However, its role in DLBCL and related mechanisms have not been reported so far. Our study reveals the expression, function and clinical significance of eccDNA in DLBCL for the first time, clarifies the mechanism of eccDNA-mediated STING pathway activation in disease progression and drug resistance, and provides a new theoretical basis for clinical treatment and prognosis evaluation of DLBCL.
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Petito, Valentina, Federica Di Vincenzo, Lorenza Putignani, Maria T. Abreu, Birgitte Regenberg, Antonio Gasbarrini i Franco Scaldaferri. "Extrachromosomal Circular DNA: An Emerging Potential Biomarker for Inflammatory Bowel Diseases?" Genes 15, nr 4 (26.03.2024): 414. http://dx.doi.org/10.3390/genes15040414.
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Inflammatory bowel disease (IBD) comprising ulcerative colitis and Crohn’s disease is a chronic immune-mediated disease which affects the gastrointestinal tract with a relapsing and remitting course, causing lifelong morbidity. IBD pathogenesis is determined by multiple factors including genetics, immune and microbial factors, and environmental factors. Although therapy options are expanding, remission rates are unsatisfiable, and together with the disease course, response to therapy remains unpredictable. Therefore, the identification of biomarkers that are predictive for the disease course and response to therapy is a significant challenge. Extrachromosomal circular DNA (eccDNA) fragments exist in all tissue tested so far. These fragments, ranging in length from a few hundreds of base pairs to mega base pairs, have recently gained more interest due to technological advances. Until now, eccDNA has mainly been studied in relation to cancer due to its ability to act as an amplification site for oncogenes and drug resistance genes. However, eccDNA could also play an important role in inflammation, expressed both locally in the- involved tissue and at distant sites. Here, we review the current evidence on the molecular mechanisms of eccDNA and its role in inflammation and IBD. Additionally, the potential of eccDNA as a tissue or plasma marker for disease severity and/or response to therapy is evaluated.
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Gerovska, Daniela, i Marcos J. Araúzo-Bravo. "Skeletal Muscles of Sedentary and Physically Active Aged People Have Distinctive Genic Extrachromosomal Circular DNA Profiles". International Journal of Molecular Sciences 24, nr 3 (1.02.2023): 2736. http://dx.doi.org/10.3390/ijms24032736.
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To bring new extrachromosomal circular DNA (eccDNA) enrichment technologies closer to the clinic, specifically for screening, early diagnosis, and monitoring of diseases or lifestyle conditions, it is paramount to identify the differential pattern of the genic eccDNA signal between two states. Current studies using short-read sequenced purified eccDNA data are based on absolute numbers of unique eccDNAs per sample or per gene, length distributions, or standard methods for RNA-seq differential analysis. Previous analyses of RNA-seq data found significant transcriptomics difference between sedentary and active life style skeletal muscle (SkM) in young people but very few in old. The first attempt using circulomics data from SkM and blood of aged lifelong sedentary and physically active males found no difference at eccDNA level. To improve the capability of finding differences between circulomics data groups, we designed a computational method to identify Differentially Produced per Gene Circles (DPpGCs) from short-read sequenced purified eccDNA data based on the circular junction, split-read signal, of the eccDNA, and implemented it into a software tool DifCir in Matlab. We employed DifCir to find to the distinctive features of the influence of the physical activity or inactivity in the aged SkM that would have remained undetected by transcriptomics methods. We mapped the data from tissue from SkM and blood from two groups of aged lifelong sedentary and physically active males using Circle_finder and subsequent merging and filtering, to find the number and length distribution of the unique eccDNA. Next, we used DifCir to find up-DPpGCs in the SkM of the sedentary and active groups. We assessed the functional enrichment of the DPpGCs using Disease Gene Network and Gene Set Enrichment Analysis. To find genes that produce eccDNA in a group without comparison with another group, we introduced a method to find Common PpGCs (CPpGCs) and used it to find CPpGCs in the SkM of the sedentary and active group. Finally, we found the eccDNA that carries whole genes. We discovered that the eccDNA in the SkM of the sedentary group is not statistically different from that of physically active aged men in terms of number and length distribution of eccDNA. In contrast, with DifCir we found distinctive gene-associated eccDNA fingerprints. We identified statistically significant up-DPpGCs in the two groups, with the top up-DPpGCs shed by the genes AGBL4, RNF213, DNAH7, MED13, and WWTR1 in the sedentary group, and ZBTB7C, TBCD, ITPR2, and DDX11-AS1 in the active group. The up-DPpGCs in both groups carry mostly gene fragments rather than whole genes. Though the subtle transcriptomics difference, we found RYR1 to be both transcriptionally up-regulated and up-DPpGCs gene in sedentary SkM. DifCir emphasizes the high sensitivity of the circulome compared to the transcriptome to detect the molecular fingerprints of exercise in aged SkM. It allows efficient identification of gene hotspots that excise more eccDNA in a health state or disease compared to a control condition.
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Kumar, Pankaj, Shashi Kiran, Shekhar Saha, Zhangli Su, Teressa Paulsen, Ajay Chatrath, Yoshiyuki Shibata, Etsuko Shibata i Anindya Dutta. "ATAC-seq identifies thousands of extrachromosomal circular DNA in cancer and cell lines". Science Advances 6, nr 20 (maj 2020): eaba2489. http://dx.doi.org/10.1126/sciadv.aba2489.
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Extrachromosomal circular DNAs (eccDNAs) are somatically mosaic and contribute to intercellular heterogeneity in normal and tumor cells. Because short eccDNAs are poorly chromatinized, we hypothesized that they are sequenced by tagmentation in ATAC-seq experiments without any enrichment of circular DNA. Indeed, ATAC-seq identified thousands of eccDNAs in cell lines that were validated by inverse PCR and by metaphase FISH. ATAC-seq in gliomas and glioblastomas identify hundreds of eccDNAs, including one containing the well-known EGFR gene amplicon from chr7. More than 18,000 eccDNAs, many carrying known cancer driver genes, are identified in a pan-cancer analysis of ATAC-seq libraries from 23 tumor types. Somatically mosaic eccDNAs are identified by ATAC-seq even before amplification is recognized by genome-wide copy number variation measurements. Thus, ATAC-seq is a sensitive method to detect eccDNA present in a tumor at the pre-amplification stage and can be used to predict resistance to therapy.
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Tsiakanikas, Panagiotis, Konstantina Athanasopoulou, Ioanna A. Darioti, Vasiliki Taxiarchoula Agiassoti, Stamatis Theocharis, Andreas Scorilas i Panagiotis G. Adamopoulos. "Beyond the Chromosome: Recent Developments in Decoding the Significance of Extrachromosomal Circular DNA (eccDNA) in Human Malignancies". Life 14, nr 8 (24.07.2024): 922. http://dx.doi.org/10.3390/life14080922.
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Extrachromosomal circular DNA (eccDNA) is a form of a circular double-stranded DNA that exists independently of conventional chromosomes. eccDNA exhibits a broad and random distribution across eukaryotic cells and has been associated with tumor-related properties due to its ability to harbor the complete gene information of oncogenes. The complex and multifaceted mechanisms underlying eccDNA formation include pathways such as DNA damage repair, breakage–fusion–bridge (BFB) mechanisms, chromothripsis, and cell apoptosis. Of note, eccDNA plays a pivotal role in tumor development, genetic heterogeneity, and therapeutic resistance. The high copy number and transcriptional activity of oncogenes carried by eccDNA contribute to the accelerated growth of tumors. Notably, the amplification of oncogenes on eccDNA is implicated in the malignant progression of cancer cells. The improvement of high-throughput sequencing techniques has greatly enhanced our knowledge of eccDNA by allowing for a detailed examination of its genetic structures and functions. However, we still lack a comprehensive and efficient annotation for eccDNA, while challenges persist in the study and understanding of the functional role of eccDNA, emphasizing the need for the development of robust methodologies. The potential clinical applications of eccDNA, such as its role as a measurable biomarker or therapeutic target in diseases, particularly within the spectrum of human malignancies, is a promising field for future research. In conclusion, eccDNA represents a quite dynamic and multifunctional genetic entity with far-reaching implications in cancer pathogenesis and beyond. Further research is essential to unravel the molecular pathways of eccDNA formation, elucidate its functional roles, and explore its clinical applications. Addressing these aspects is crucial for advancing our understanding of genomic instability and developing novel strategies for tailored therapeutics, especially in cancer.
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He, Haobin, Zihan Gao, Zehua Hu, Guanyu Liang, Yanhua Huang, Meng Zhou, Rishen Liang i Kai Zhang. "Identification and Characterization of Extrachromosomal Circular DNA in Slimming Grass Carp". Biomolecules 14, nr 9 (23.08.2024): 1045. http://dx.doi.org/10.3390/biom14091045.
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Slimming grass carp is a commercial variety with good body form and meat quality, which is cultured by starving common grass carp in a clean flowing water environment. Compared to common grass carp, slimming grass carp has a far higher economic value. Until now, no molecular study has concentrated on the regulation mechanism of the muscle characteristics of slimming grass carp. This study first reported the gene expression profile of the muscle characteristics of slimming grass carp based on the level of extrachromosomal circular DNAs (eccDNAs). EccDNAs are double-stranded circular DNAs derived from genomic DNAs and play crucial roles in the functional regulation of a wide range of biological processes, none of which have been shown to occur in fish. Here, muscle eccDNAs from slimming grass carp and common grass carp were both generally sequenced, and the information, as well as the expression profile of eccDNAs, were compared and analysed. The findings reveal that 82,238 and 25,857 eccDNAs were detected from slimming grass carp and common grass carp, respectively. The length distribution of eccDNAs was in the range of 1~1000 bp, with two peaks at about 200 bp and 400 bp. When the expression profiles of eccDNAs between slimming grass carp and common grass carp were compared, 3523 up-regulated and 175 down-regulated eccDNAs were found. Enrichment analysis showed that these eccDNA genes were correlated with cellular structure and response, cell immunology, enzyme activity, etc. Certain differentially expressed eccDNAs involved in muscle characteristics were detected, which include myosin heavy chain, myosin light chain, muscle segment homeobox C, calsequestrin, calmodulin, etc., among which the majority of genes were linked to muscle structure and contraction. This indicates that during the process of cultivating from common grass carp to slimming grass carp, the treatment primarily affected muscle structure and contraction, making the meat quality of slimming grass carp different from that of common grass carp. This result provides molecular evidence and new insights by which to elucidate the regulating mechanism of muscle phenotypic characterisation in slimming grass carp and other fish.
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Gerovska, Daniela, i Marcos J. Araúzo-Bravo. "Systemic Lupus Erythematosus Patients with DNASE1L3·Deficiency Have a Distinctive and Specific Genic Circular DNA Profile in Plasma". Cells 12, nr 7 (31.03.2023): 1061. http://dx.doi.org/10.3390/cells12071061.
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Cell-free (cf) extrachromosomal circular DNA (eccDNA) has a potential clinical application as a biomarker. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a complex immunological pathogenesis, associated with autoantibody synthesis. A previous study found that SLE patients with deoxyribonuclease 1-like 3 (DNASE1L3) deficiency exhibit changes in the frequency of short and long eccDNA in plasma compared to controls. Here, using the DifCir method for differential analysis of short-read sequenced purified eccDNA data based on the split-read signal of the eccDNA on circulomics data, we show that SLE patients with DNASE1L3 deficiency have a distinctive profile of eccDNA excised by gene regions compared to controls. Moreover, this profile is specific; cf-eccDNA from the top 93 genes is detected in all SLE with DNASE1L3 deficiency samples, and none in the control plasma. The top protein coding gene producing eccDNA-carrying gene fragments is the transcription factor BARX2, which is involved in skeletal muscle morphogenesis and connective tissue development. The top gene ontology terms are ‘positive regulation of torc1 signaling’ and ‘chondrocyte development’. The top Harmonizome terms are ‘lymphopenia’, ‘metabolic syndrome x’, ‘asthma’, ‘cardiovascular system disease‘, ‘leukemia’, and ‘immune system disease’. Here, we show that gene associations of cf-eccDNA can serve as a biomarker in the autoimmune rheumatic diseases.
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Di Vincenzo, Federica, Ylenia Yadid, Valentina Petito, Valeria Emoli, Letizia Masi, Daniela Gerovska, Marcos Jesus Araúzo-Bravo, Antonio Gasbarrini, Birgitte Regenberg i Franco Scaldaferri. "Circular and Circulating DNA in Inflammatory Bowel Disease: From Pathogenesis to Potential Molecular Therapies". Cells 12, nr 15 (27.07.2023): 1953. http://dx.doi.org/10.3390/cells12151953.
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Inflammatory bowel diseases (IBD), including Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic multifactorial disorders which affect the gastrointestinal tract with variable extent. Despite extensive research, their etiology and exact pathogenesis are still unknown. Cell-free DNAs (cfDNAs) are defined as any DNA fragments which are free from the origin cell and able to circulate into the bloodstream with or without microvescicles. CfDNAs are now being increasingly studied in different human diseases, like cancer or inflammatory diseases. However, to date it is unclear how IBD etiology is linked to cfDNAs in plasma. Extrachromosomal circular DNA (eccDNA) are non-plasmidic, nuclear, circular and closed DNA molecules found in all eukaryotes tested. CfDNAs appear to play an important role in autoimmune diseases, inflammatory processes, and cancer; recently, interest has also grown in IBD, and their role in the pathogenesis of IBD has been suggested. We now suggest that eccDNAs also play a role in IBD. In this review, we have comprehensively collected available knowledge in literature regarding cfDNA, eccDNA, and structures involving them such as neutrophil extracellular traps and exosomes, and their role in IBD. Finally, we focused on old and novel potential molecular therapies and drug delivery systems, such as nanoparticles, for IBD treatment.
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Foscarini, E., V. Emoli, V. Petito, F. Di Vincenzo, L. Masi, S. Troisi, C. Pane i in. "P0167 Circular extrachromosomal DNA (eccDNA): a potential diagnostic and prognostic tool to be introduced into the clinical practice of Inflammatory Bowel Disease". Journal of Crohn's and Colitis 19, Supplement_1 (styczeń 2025): i563—i564. https://doi.org/10.1093/ecco-jcc/jjae190.0341.
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Abstract Background The diagnosis of Inflammatory Bowel Disease, which continues to increase year by year, is complex; these disorders can be confirmed by investigations such as fecal calprotectin, endoscopy, histology of biopsies, and CT scan; despite this, there is a lack of highly specific and minimally invasive techniques that allow not only diagnosis but also determination of the severity of the disease and its evolution. Given these challenges, the search for reliable and specific predictors that can direct the clinician toward personalized patient care is very important. In this context, can help extrachromosomal circular DNA (eccDNA) that are eukaryotic nuclear circle DNA molecules, independent from chromosomes, with a length ranging from a few hundred to a few thousand base pairs. In addition to its already known role in cancer, in IBD increased levels of eccDNA have been found compared with healthy controls. Circular DNA could represent a potential biomarker that can be isolated from peripheral blood or intestinal mucosa and is useful for making early diagnoses and assessing disease status. Methods We examined peripheral blood, collected by blood sampling . "Technical Tests" were performed in order to determine the right procedure for storing blood samples and optimize the results obtained in terms of eccDNA extraction . The samples will be divided into two groups, for the first group the procedure is to centrifuge the blood at 2000g for 15 minutes at different timepoints with or without storing the plasma at 4° C; for the second group the sample is centrifuged immediately after blood collection and the plasma is stored in the refrigerator at different timepoints [Table 1]. Then for both groups we proceed with eccDNA extraction by the "Circle-Seq" analysis. Results No significant differences are shown between the two groups in terms of the amount of eccDNA [Figure 1]. In particular, the non-immediate centrifugation and separation of plasma from whole blood does not negatively affect the extraction yield, highlighting that degradative factors are not present in whole blood. In addition, refrigerated storage for a longer period of time is a positive factor for eccDNA concentration, probably because in this way circular DNA found within microvesicles has time to be extruded, increasing its concentration in plasma. Conclusion Circulating eccDNAs could represent potential biomarkers to be detected in plasma by liquid biopsy, as the method is minimally invasive and easily reproducible in analytical laboratories, becoming a diagnostic and prognostic tool to be brought into clinical practice. References Fundings: European Union’s Horizon 2020 Research and Innovation Programme (899417)
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Gerovska, Daniela, Patricia Fernández Moreno, Aitor Zabala i Marcos J. Araúzo-Bravo. "Cell-Free Genic Extrachromosomal Circular DNA Profiles of DNase Knockouts Associated with Systemic Lupus Erythematosus and Relation with Common Fragile Sites". Biomedicines 12, nr 1 (28.12.2023): 80. http://dx.doi.org/10.3390/biomedicines12010080.
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Cell-free extrachromosomal circular DNA (cf-eccDNA) has been proposed as a promising early biomarker for disease diagnosis, progression and drug response. Its established biomarker features are changes in the number and length distribution of cf-eccDNA. Another novel promising biomarker is a set of eccDNA excised from a panel of genes specific to a condition compared to a control. Deficiencies in two endonucleases that specifically target DNA, Dnase1 and Dnase1l3, are associated with systemic lupus erythematosus (SLE). To study the genic eccDNA profiles in the case of their deficiencies, we mapped sequenced eccDNA data from plasma, liver and buffy coat from Dnase1 and Dnase1l3 knockouts (KOs), and wild type controls in mouse. Next, we performed an eccDNA differential analysis between KO and control groups using our DifCir algorithm. We found a specific genic cf-eccDNA fingerprint of the Dnase1l3 group compared to the wild type controls involving 131 genes; 26% of them were associated with human chromosomal fragile sites (CFSs) and with a statistically significant enrichment of CFS-associated genes. We found six genes in common with the genic cf-eccDNA profile of SLE patients with DNASE1L3 deficiency, namely Rorb, Mvb12b, Osbpl10, Fto, Tnik and Arhgap10; all of them were specific and present in all human plasma samples, and none of them were associated with CFSs. A not so distinctive genic cf-eccDNA difference involving only seven genes was observed in the case of the Dnase1 group compared to the wild type. In tissue—liver and buffy coat—we did not detect the same genic eccDNA difference observed in the plasma samples. These results point to a specific role of a set of genic eccDNA in plasma from DNase KOs, as well as a relation with CFS genes, confirming the promise of the genic cf-eccDNA in studying diseases and the need for further research on the relationship between eccDNA and CFSs.
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Emoli, V., E. Foscarini, F. Di Vincenzo, L. Masi, S. Troisi, C. Pane, G. Migliore i in. "P0036 NRG1, a gene significantly detected from intestinal mucosa eccDNA, may predict therapeutic response in Inflammatory Bowel Disease". Journal of Crohn's and Colitis 19, Supplement_1 (styczeń 2025): i381. https://doi.org/10.1093/ecco-jcc/jjae190.0210.
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Abstract Background Many patients with Inflammatory Bowel Diseases do not respond to biological therapies. Extrachromosomal circular DNA(eccDNA) has been showed to play a role in the pathophysiology of IBD, as there is a higher presence of eccDNA in the intestinal mucosa of these patients. By characterizing the gene content of eccDNA, up-regulation of certain genes is observed; one of these is NRG1 (Neuregulin 1), an EGF ligand that guides tissue repair after injury and is associated with tissue plasticity. This gene is located on chromosome 8p12 and it is expressed in macrophages, Paneth cells, and stromal mesenchymal cells of the stem cell niche. In the context of IBD, where chronic inflammation is a hallmark, NRG1 could potentially modulate the immune response to reduce inflammation and promote healing. It is important to understand whether its expression within eccDNA may correlate with a particular course of the disease. Methods eccDNA was extracted from intestinal mucosa samples derived from patients diagnosed with IBD and amplified using the Circle-Seq analysis. Following sequencing, bioinformatic interpretation of the data was performed, through which a list of gene fragments present on the circles of individual patients and their localization was obtained. Finally, the presence of the gene found up-regulated by the bioinformatic analysis was confirmed using Real Time PCR. Results Starting from 99 intestinal mucosa samples from IBD patients, whose eccDNA was sequenced, circles containing fragments of NRG1 were found in 22 of them; its presence was compared to samples of diseased mucosa biopsies versus healthy mucosa from the same IBD patient. The number of circles from NRG1 is greater in diseased mucosa samples compared to healthy ones, in both UC and CD patients. Furthermore stratifying patients by response to therapy, about 70% of responders to IBD-therapy were NRG1- , with Odds Ratio <1. Conclusion Preliminary results show that NRG1, a gene significantly detected from intestinal mucosa eccDNA, may predict therapeutic response in Inflammatory Bowel Disease. Further analysis are needed to confirm these data. References 1.Di Vincenzo F, Yadid Y, Petito V. et al. Circular and Circulating DNA in Inflammatory Bowel Disease: From Pathogenesis to Potential Molecular Therapies. Cells. 2023 Jul 27;12(15):1953. 2.Møller H.D., Bojsen RK., Tachibana C. et al. Genome-wide Purification of Extrachromosomal Circular DNA from Eukaryotic Cells. J Vis Exp. 2016 Apr 4;(110):e54239 3.Møller H.D., Mohiyuddin M., Prada-Luengo I. et al. Circular DNA elements of chromosomal origin are common in healthy human somatic tissue. Nat Commun 9, 1069 (2018).
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Hull, Ryan M., i Jonathan Houseley. "The adaptive potential of circular DNA accumulation in ageing cells". Current Genetics 66, nr 5 (15.04.2020): 889–94. http://dx.doi.org/10.1007/s00294-020-01069-9.
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Abstract Carefully maintained and precisely inherited chromosomal DNA provides long-term genetic stability, but eukaryotic cells facing environmental challenges can benefit from the accumulation of less stable DNA species. Circular DNA molecules lacking centromeres segregate randomly or asymmetrically during cell division, following non-Mendelian inheritance patterns that result in high copy number instability and massive heterogeneity across populations. Such circular DNA species, variously known as extrachromosomal circular DNA (eccDNA), microDNA, double minutes or extrachromosomal DNA (ecDNA), are becoming recognised as a major source of the genetic variation exploited by cancer cells and pathogenic eukaryotes to acquire drug resistance. In budding yeast, circular DNA molecules derived from the ribosomal DNA (ERCs) have been long known to accumulate with age, but it is now clear that aged yeast also accumulate other high-copy protein-coding circular DNAs acquired through both random and environmentally-stimulated recombination processes. Here, we argue that accumulation of circular DNA provides a reservoir of heterogeneous genetic material that can allow rapid adaptation of aged cells to environmental insults, but avoids the negative fitness impacts on normal growth of unsolicited gene amplification in the young population.
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Kumar, Pankaj, Laura W. Dillon, Yoshiyuki Shibata, Amir A. Jazaeri, David R. Jones i Anindya Dutta. "Normal and Cancerous Tissues Release Extrachromosomal Circular DNA (eccDNA) into the Circulation". Molecular Cancer Research 15, nr 9 (26.05.2017): 1197–205. http://dx.doi.org/10.1158/1541-7786.mcr-17-0095.
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Shoura, Massa, Stephen Levene i Andrew Fire. "Circulomics: Ultrasensitive Characterization of Extrachromosomal Circular DNA (eccDNA) Distributions and Functions in Eukaryotes". Biophysical Journal 114, nr 3 (luty 2018): 83a. http://dx.doi.org/10.1016/j.bpj.2017.11.499.
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Paulsen, Teressa, Pumoli Malapati, Yoshiyuki Shibata, Briana Wilson, Rebeka Eki, Mouadh Benamar, Tarek Abbas i Anindya Dutta. "MicroDNA levels are dependent on MMEJ, repressed by c-NHEJ pathway, and stimulated by DNA damage". Nucleic Acids Research 49, nr 20 (30.10.2021): 11787–99. http://dx.doi.org/10.1093/nar/gkab984.
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Abstract Extrachromosomal circular DNA (eccDNA) are present within all eukaryotic organisms and actively contribute to gene expression changes. MicroDNA (200-1000bp) are the most abundant type of eccDNA and can amplify tRNA, microRNA, and novel si-like RNA sequences. Due to the heterogeneity of microDNA and the limited technology to directly quantify circular DNA molecules, the specific DNA repair pathways that contribute to microDNA formation have not been fully elucidated. Using a sensitive and quantitative assay that quantifies eight known abundant microDNA, we report that microDNA levels are dependent on resection after double-strand DNA break (DSB) and repair by Microhomology Mediated End Joining (MMEJ). Further, repair of DSB without resection by canonical Non-Homologous End Joining (c-NHEJ) diminishes microDNA formation. MicroDNA levels are induced locally even by a single site-directed DSB, suggesting that excision of genomic DNA by two closely spaced DSB is not necessary for microDNA formation. Consistent with all this, microDNA levels accumulate as cells undergo replication in S-phase, when DNA breaks and repair are elevated, and microDNA levels are decreased if DNA synthesis is prevented. Thus, formation of microDNA occurs during the repair of endogenous or induced DNA breaks by resection-based DNA repair pathways.
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Koo, Dal-Hoe, Rajendran Sathishraj, Bernd Friebe i Bikram S. Gill. "Deciphering the Mechanism of Glyphosate Resistance in <b><i>Amaranthus palmeri</i></b> by Cytogenomics". Cytogenetic and Genome Research 161, nr 12 (2021): 578–84. http://dx.doi.org/10.1159/000521409.
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In agriculture, various chemicals are used to control the weeds. Out of which, glyphosate is an important herbicide invariably used in the cultivation of glyphosate-resistant crops to control weeds. Overuse of glyphosate results in the evolution of glyphosate-resistant weeds. Evolution of glyphosate resistance (GR) in <i>Amaranthus palmeri</i> (AP) is a serious concern in the USA. Investigation of the mechanism of GR in AP identified different resistance mechanisms of which <i>5-enolpyruvylshikimate-3-phosphate synthase</i> (<i>EPSPS</i>) gene amplification is predominant. Molecular analysis of GR AP identified the presence of a 5- to >160-fold increase in copies of the <i>EPSPS</i> gene than in a glyphosate-susceptible (GS) population. This increased copy number of the <i>EPSPS</i> gene increased the genome size ranging from 3.5 to 11.8%, depending on the copy number compared to the genome size of GS AP. FISH analysis using a 399-kb <i>EPSPS</i> cassette derived from bacterial artificial chromosomes (BACs) as probes identified that amplified <i>EPSPS</i> copies in GR AP exist in extrachromosomal circular DNA (eccDNA) in addition to the native copy in the chromosome. The <i>EPSPS</i> gene-containing eccDNA having a size of ∼400 kb is termed <i>EPSPS</i>-eccDNA and showed somatic mosacism in size and copy number. <i>EPSPS</i>-eccDNA has a genetic mechanism to tether randomly to mitotic or meiotic chromosomes during cell division or gamete formation and is inherited to daughter cells or progeny generating copy number variation. These eccDNAs are stable genetic elements that can replicate and exist independently. The genomic characterization of the <i>EPSPS</i> locus, along with the flanking regions, identified the presence of a complex array of repeats and mobile genetic elements. The cytogenomics approach in understanding the biology of <i>EPSPS</i>-eccDNA sheds light on various characteristics of <i>EPSPS</i>-eccDNA that favor GR in AP.
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de Alteriis, Elisabetta, Guido Incerti, Fabrizio Cartenì, Maria Luisa Chiusano, Chiara Colantuono, Emanuela Palomba, Pasquale Termolino i in. "Extracellular DNA secreted in yeast cultures is metabolism-specific and inhibits cell proliferation". Microbial Cell 10, nr 12 (4.12.2023): 277–95. http://dx.doi.org/10.15698/mic2023.12.810.
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Extracellular DNA (exDNA) can be actively released by living cells and different putative functions have been attributed to it. Further, homologous exDNA has been reported to exert species-specific inhibitory effects on several organisms. Here, we demonstrate by different experimental evidence, including 1H-NMR metabolomic fingerprint, that the growth rate decline in Saccharomyces cerevisiae fed-batch cultures is determined by the accumulation of exDNA in the medium. Sequencing of such secreted exDNA represents a portion of the entire genome, showing a great similarity with extrachromosomal circular DNA (eccDNA) already reported inside yeast cells. The recovered DNA molecules were mostly single strands and specifically associated to the yeast metabolism displayed during cell growth. Flow cytometric analysis showed that the observed growth inhibition by exDNA corresponded to an arrest in the S phase of the cell cycle. These unprecedented findings open a new scenario on the functional role of exDNA produced by living cells.
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Chitwood, Dylan G., Lisa Uy, Wanfang Fu, Stephanie R. Klaubert, Sarah W. Harcum i Christopher A. Saski. "Dynamics of Amino Acid Metabolism, Gene Expression, and Circulomics in a Recombinant Chinese Hamster Ovary Cell Line Adapted to Moderate and High Levels of Extracellular Lactate". Genes 14, nr 8 (2.08.2023): 1576. http://dx.doi.org/10.3390/genes14081576.
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The accumulation of metabolic wastes in cell cultures can diminish product quality, reduce productivity, and trigger apoptosis. The limitation or removal of unintended waste products from Chinese hamster ovary (CHO) cell cultures has been attempted through multiple process and genetic engineering avenues with varied levels of success. One study demonstrated a simple method to reduce lactate and ammonia production in CHO cells with adaptation to extracellular lactate; however, the mechanism behind adaptation was not certain. To address this profound gap, this study characterizes the phenotype of a recombinant CHO K-1 cell line that was gradually adapted to moderate and high levels of extracellular lactate and examines the genomic content and role of extrachromosomal circular DNA (eccDNA) and gene expression on the adaptation process. More than 500 genes were observed on eccDNAs. Notably, more than 1000 genes were observed to be differentially expressed at different levels of lactate adaptation, while only 137 genes were found to be differentially expressed between unadapted cells and cells adapted to grow in high levels of lactate; this suggests stochastic switching as a potential stress adaptation mechanism in CHO cells. Further, these data suggest alanine biosynthesis as a potential stress-mitigation mechanism for excess lactate in CHO cells.
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Dehm, Scott M. "Abstract IA003: Evolution of AR gene structure during prostate cancer progression". Cancer Research 83, nr 11_Supplement (2.06.2023): IA003. http://dx.doi.org/10.1158/1538-7445.prca2023-ia003.
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Abstract Castration-resistant prostate cancer (CRPC) emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. Our laboratory has implemented DNA sequencing approaches to identify genomic mechanisms contributing to CRPC in prostate cancer cell lines, patient-derived xenografts (PDXs), and clinical specimens. These approaches have revealed AR as one of the most frequently-rearranged genes in CRPC. However the patterns of AR gene rearrangements observed between patients and even between anatomically distinct metastases within a single patient are remarkably complex and heterogeneous. To address this complexity, we analyzed a cohort of prostate cancer specimens using linked-read DNA-sequencing. This approach found that a subset of clinical CRPC metastases had accumulated complex AR rearrangements in conjunction with very high AR copy number, a phenomenon that also occurred in PDX models grown under selective pressure of castration. Using orthogonal approaches of optical genome mapping and fluorescence in situ hybridization, we found that AR residing on extrachromosomal circular DNA (eccDNA) was an underlying mechanism. This study identifies eccDNA as an engine for accumulation of AR gene copy number and structural complexity during CRPC progression. Citation Format: Scott M Dehm. Evolution of AR gene structure during prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA003.
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Koo, Dal-Hoe, William T. Molin, Christopher A. Saski, Jiming Jiang, Karthik Putta, Mithila Jugulam, Bernd Friebe i Bikram S. Gill. "Extrachromosomal circular DNA-based amplification and transmission of herbicide resistance in crop weedAmaranthus palmeri". Proceedings of the National Academy of Sciences 115, nr 13 (12.03.2018): 3332–37. http://dx.doi.org/10.1073/pnas.1719354115.
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Gene amplification has been observed in many bacteria and eukaryotes as a response to various selective pressures, such as antibiotics, cytotoxic drugs, pesticides, herbicides, and other stressful environmental conditions. An increase in gene copy number is often found as extrachromosomal elements that usually contain autonomously replicating extrachromosomal circular DNA molecules (eccDNAs).Amaranthus palmeri, a crop weed, can develop herbicide resistance to glyphosate [N-(phosphonomethyl) glycine] by amplification of the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene, the molecular target of glyphosate. However, biological questions regarding the source of the amplifiedEPSPS, the nature of the amplified DNA structures, and mechanisms responsible for maintaining this gene amplification in cells and their inheritance remain unknown. Here, we report that amplifiedEPSPScopies in glyphosate-resistant (GR)A. palmeriare present in the form of eccDNAs with various conformations. The eccDNAs are transmitted during cell division in mitosis and meiosis to the soma and germ cells and the progeny by an as yet unknown mechanism of tethering to mitotic and meiotic chromosomes. We propose that eccDNAs are one of the components of McClintock’s postulated innate systems [McClintock B (1978)Stadler Genetics Symposium] that can rapidly produce soma variation, amplifyEPSPSgenes in the sporophyte that are transmitted to germ cells, and modulate rapid glyphosate resistance through genome plasticity and adaptive evolution.
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Tapia-Pastrana, Fernando. "Cytogenetics of Diphysa americana (Mill.) M.Sousa (Leguminosae-Papilionoideae-dalbergioid clade), a rare species from the coast of Oaxaca, Mexico". Caryologia 76, nr 2 (31.12.2023): 51–57. http://dx.doi.org/10.36253/caryologia-2300.
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Diphysa Jacq. is an essentially Mexican and Central American genus that includes 21 species and only one cytogenetic report. In this work, a surface spread and air-drying method was used to obtain the karyotype of Diphysa americana (Mill) M.Sousa, a rare native tree that grows in a coastal town in the State of Oaxaca, Mexico. Metaphase cells showed a 2n = 20, consistent with the predominant diploid number in the dalbergioid clade. This number contrasts with a previously reported 2n = 16. The karyotypic formula 5m + 5sm, first proposed for a species of the genus, denotes a slightly asymmetric karyotype. The presence of secondary constrictions associated with satellites on the short arms of a pair of sm chromosomes and other cytogenetic parameters require studies in other species of the genus to verify their taxonomic utility. In addition, cells in prometaphase exhibited a circular fragment of unknown origin like that observed in a species of the genus Aeschynomene, also dalbergioid. This fragment could be related to extrachromosomal circular DNA (eccDNA) observed in other plants. Diphysa is a small, cytogenetically favorable genus, and further studies will exhibit the karyotypic diversity that underlies its diversification.
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Zhuang, Jundong, Yaoxin Zhang, Congcong Zhou, Danlin Fan, Tao Huang, Qi Feng, Yiqi Lu i in. "Dynamics of extrachromosomal circular DNA in rice". Nature Communications 15, nr 1 (18.03.2024). http://dx.doi.org/10.1038/s41467-024-46691-0.
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AbstractThe genome’s dynamic nature, exemplified by elements like extrachromosomal circular DNA (eccDNA), is crucial for biodiversity and adaptation. Yet, the role of eccDNA in plants, particularly rice, remains underexplored. Here, we identify 25,598 eccDNAs, unveiling the widespread presence of eccDNA across six rice tissues and revealing its formation as a universal and random process. Interestingly, we discover that direct repeats play a pivotal role in eccDNA formation, pointing to a unique origin mechanism. Despite eccDNA’s prevalence in coding sequences, its impact on gene expression is minimal, implying its roles beyond gene regulation. We also observe the association between eccDNA’s formation and minor chromosomal deletions, providing insights of its possible function in regulating genome stability. Further, we discover eccDNA specifically accumulated in rice leaves, which may be associated with DNA damage caused by environmental stressors like intense light. In summary, our research advances understanding of eccDNA’s role in the genomic architecture and offers valuable insights for rice cultivation and breeding.
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Peng, Li, Nan Zhou, Chao-Yang Zhang, Guan-Cheng Li i Xiao-Qing Yuan. "eccDNAdb: a database of extrachromosomal circular DNA profiles in human cancers". Oncogene, 6.04.2022. http://dx.doi.org/10.1038/s41388-022-02286-x.
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AbstractExtrachromosomal circular DNA (eccDNA) elements are circular DNA molecules that are derived from but are independent of chromosomal DNA. EccDNA is emerging as a rising star because of its ubiquitous existence in cancers and its crucial role in oncogene amplification and tumor progression. In the present study, whole-genome sequencing (WGS) data of cancer samples were downloaded from public repositories. Afterwards, eccDNAs were identified from WGS data via bioinformatic analyses. To leverage database coverage, eccDNAs were also collected by manual curation of literatures. Gene expression and clinical data were downloaded from TCGA and CCLE and then used to investigate the roles of eccDNAs in cancers. Finally, the first integrated database of eccDNAs, eccDNAdb, was developed. eccDNAdb currently includes 1270 eccDNAs, which were identified in 480 samples (of 42 cancers) after analyzing a total number of 3395 tumor samples (of 57 cancers) including patient tissues, patient-derived xenografts, and cancer cell lines. A total number of 54,901 eccDNA genes were annotated and included in the database as well. With the integration of gene expression, clinical information and chromatin accessibility data, eccDNAdb enables users to easily determine the biological function and clinical relevance of eccDNAs in human cancers. In conclusion, eccDNAdb is freely accessible at http://www.eccdnadb.org. To our knowledge, eccDNAdb is the first database in the eccDNA research field. It is expected to provide insight for novel cancer therapies.
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Yang, Ludi, Ruobing Jia, Tongxin Ge, Shengfang Ge, Ai Zhuang, Peiwei Chai i Xianqun Fan. "Extrachromosomal circular DNA: biogenesis, structure, functions and diseases". Signal Transduction and Targeted Therapy 7, nr 1 (2.10.2022). http://dx.doi.org/10.1038/s41392-022-01176-8.
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AbstractExtrachromosomal circular DNA (eccDNA), ranging in size from tens to millions of base pairs, is independent of conventional chromosomes. Recently, eccDNAs have been considered an unanticipated major source of somatic rearrangements, contributing to genomic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. In addition, the origin of eccDNA is considered to be associated with essential chromatin-related events, including the formation of super-enhancers and DNA repair machineries. Moreover, our understanding of the properties and functions of eccDNA has continuously and greatly expanded. Emerging investigations demonstrate that eccDNAs serve as multifunctional molecules in various organisms during diversified biological processes, such as epigenetic remodeling, telomere trimming, and the regulation of canonical signaling pathways. Importantly, its special distribution potentiates eccDNA as a measurable biomarker in many diseases, especially cancers. The loss of eccDNA homeostasis facilitates tumor initiation, malignant progression, and heterogeneous evolution in many cancers. An in-depth understanding of eccDNA provides novel insights for precision cancer treatment. In this review, we summarized the discovery history of eccDNA, discussed the biogenesis, characteristics, and functions of eccDNA. Moreover, we emphasized the role of eccDNA during tumor pathogenesis and malignant evolution. Therapeutically, we summarized potential clinical applications that target aberrant eccDNA in multiple diseases.
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Cheng, Zhuo, Xuanmei Luo, Wenzheng Liu, Xiaofang Lu, Hong Chang, Yingchun Wang, Wei Zheng, Xiue Yan i Yonghui Huang. "Comprehensive landscape and oncogenic role of extrachromosomal circular DNA in malignant biliary strictures". Cell & Bioscience 15, nr 1 (7.02.2025). https://doi.org/10.1186/s13578-025-01361-6.
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Abstract Background Extrachromosomal circular DNA (eccDNA) is crucial for carcinogenesis and bile has direct contact with malignant biliary strictures, yet eccDNA features in bile and its function in malignant biliary strictures remain underexplored. Results We observed the widespread presence of eccDNA in bile and systematically profiled the landscape of bile cell-free eccDNA (bcf-eccDNA). For functional exploration, a simple and efficient workflow was designed to synthesize large eccDNA particularly containing multiple regions. Compared with the noncancer group, bcf-eccDNAs in the cancer group had different origins and larger sizes with six characteristic peaks. These peaks were also identified in the validation cohort (100%). There were more bcf-eccDNA carrying LINC00598 or CELF2 in malignant biliary strictures, showing potential diagnostic performance in training and validation cohorts (all AUCs > 0.9). Bcf-eccDNAs carried cancer-related mutations, which could guide treatment. EccDNA carrying miR-106a/363 cluster or miR-374b/421 cluster were proven to regulate cancer gene expression, accelerate tumor proliferation, and inhibit tumor apoptosis. Conclusions This study profiles a comprehensive bcf-eccDNA landscape in patients with biliary strictures and offers valuable insights into eccDNA's role in bile liquid biopsy and carcinogenesis.
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Pang, Jingyuan, Xiaoguang Pan, Ling Lin, Lei Li, Shuai Yuan, Peng Han, Xiaopeng Ji i in. "Characterization of Plasma Extrachromosomal Circular DNA in Gouty Arthritis". Frontiers in Genetics 13 (6.04.2022). http://dx.doi.org/10.3389/fgene.2022.859513.
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Objective: Extrachromosomal circular DNA elements (eccDNAs) are known for their broad existence in cells and plasma, which may potentially play important roles in many biological processes. Our aim was to identify potentially functional or marked eccDNAs in gout patients.Methods: The Circle-Seq approach was applied for eccDNA detection from plasma in acute gout patients and healthy controls. Further analysis was performed on the distribution of genomic elements and eccDNA gene annotations in two groups.Results: We detected 57,216 and 109,683 eccDNAs from the acute gout and healthy control plasma, respectively. EccDNAs were mapped to the reference genome to identify diverse classes of genomic elements and there was no significant difference of eccDNAs on genomic element annotation between gout and control group. A total of 256 eccDNA-associated genes were detected as gout unique eccDNA genes, including COL1A1 and EPB42, which potentially contribute to hyperuricemia and gout, and a couple of genes involved in inflammation or immune response. Enrichment analysis showed that these eccDNA genes were highly correlated with defense response, stress response, and immune and inflammatory responses, including T cell receptor signaling pathway, Fc epsilon RI signaling pathway, and JAK-STAT signaling pathway.Conclusion: Our discovery reveals the novel potential biological roles of plasma eccDNAs in gouty arthritis.
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Wang, Tianyi, Haijian Zhang, Youlang Zhou i Jiahai Shi. "Extrachromosomal circular DNA: a new potential role in cancer progression". Journal of Translational Medicine 19, nr 1 (10.06.2021). http://dx.doi.org/10.1186/s12967-021-02927-x.
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AbstractExtrachromosomal circular DNA (eccDNA) is considered a circular DNA molecule that exists widely in nature and is independent of conventional chromosomes. eccDNA can be divided into small polydispersed circular DNA (spcDNA), telomeric circles (t-circles), microDNA, and extrachromosomal DNA (ecDNA) according to its size and sequence. Multiple studies have shown that eccDNA is the product of genomic instability, has rich and important biological functions, and is involved in the occurrence of many diseases, including cancer. In this review, we focus on the discovery history, formation process, characteristics, and physiological functions of eccDNAs; the potential functions of various eccDNAs in human cancer; and the research methods employed to study eccDNA.
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Zhao, Yiheng, Linchan Yu, Shuchen Zhang, Xiangyu Su i Xiang Zhou. "Extrachromosomal circular DNA: Current status and future prospects". eLife 11 (18.10.2022). http://dx.doi.org/10.7554/elife.81412.
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Extrachromosomal circular DNA (eccDNA) is a double-stranded DNA molecule found in various organisms, including humans. In the past few decades, the research on eccDNA has mainly focused on cancers and their associated diseases. Advancements in modern omics technologies have reinvigorated research on eccDNA and shed light on the role of these molecules in a range of diseases and normal cell phenotypes. In this review, we first summarize the formation of eccDNA and its modes of action in eukaryotic cells. We then outline eccDNA as a disease biomarker and reveal its regulatory mechanism. We finally discuss the future prospects of eccDNA, including basic research and clinical application. Thus, with the deepening of understanding and exploration of eccDNAs, they hold great promise in future biomedical research and clinical translational application.
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Zuo, Shanru, Yihu Yi, Chen Wang, Xueguang Li, Mingqing Zhou, Qiyao Peng, Junhua Zhou, Yide Yang i Quanyuan He. "Extrachromosomal Circular DNA (eccDNA): From Chaos to Function". Frontiers in Cell and Developmental Biology 9 (6.01.2022). http://dx.doi.org/10.3389/fcell.2021.792555.
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Extrachromosomal circular DNA (eccDNA) is a type of double-stranded circular DNA that is derived and free from chromosomes. It has a strong heterogeneity in sequence, length, and origin and has been identified in both normal and cancer cells. Although many studies suggested its potential roles in various physiological and pathological procedures including aging, telomere and rDNA maintenance, drug resistance, and tumorigenesis, the functional relevance of eccDNA remains to be elucidated. Recently, due to technological advancements, accumulated evidence highlighted that eccDNA plays an important role in cancers by regulating the expression of oncogenes, chromosome accessibility, genome replication, immune response, and cellular communications. Here, we review the features, biogenesis, physiological functions, potential functions in cancer, and research methods of eccDNAs with a focus on some open problems in the field and provide a perspective on how eccDNAs evolve specific functions out of the chaos in cells.
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Chen, Kejie, Yanqi Chi, Hang Cheng, Min Yang, Quandan Tan, Junli Hao, Yapeng Lin, Fengkai Mao, Song He i Jie Yang. "Identification and characterization of extrachromosomal circular DNA in large‐artery atherosclerotic stroke". Journal of Cellular and Molecular Medicine 28, nr 7 (20.03.2024). http://dx.doi.org/10.1111/jcmm.18210.
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AbstractExtrachromosomal circular DNA (eccDNA) is a new biomarker and regulator of diseases. However, the role of eccDNAs in large‐artery atherosclerotic (LAA) stroke remains unclear. Through high‐throughput circle‐sequencing technique, the length distribution, genomic characteristic and motifs feature of plasma eccDNA from healthy controls (CON) and patients with LAA stroke were analysed. Then, the potential functions of the annotated eccDNAs were investigated using GO and KEGG pathway analyses. EccDNAs mapped to the reference genome showed SHN3 and BCL6 were LAA stroke unique transcription factors. The genes of differentially expressed eccDNAs between LAA stroke patients and CON were mainly involved in axon/dendrite/neuron projection development and maintenance of cellular structure via Wnt, Rap1 and MAPK pathways. Moreover, LAA stroke unique eccDNA genes played a role in regulation of coagulation and fibrinolysis, and there were five LAA stroke unique eccDNAs (Chr2:12724406‐12724784, Chr4:1867120‐186272046, Chr4:186271494‐186271696, Chr7:116560296‐116560685 and Chr11:57611780‐5761192). Additionally, POLR2C and AURKA carried by ecDNAs (eccDNA size >100 kb) of LAA stroke patients were significantly associated with development of LAA stroke. Our data firstly revealed the characteristics of eccDNA in LAA stroke and the functions of LAA stroke unique eccDNAs and eccDNA genes, suggesting eccDNA is a novel biomarker and mechanism of LAA stroke.
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Guo, Jing, Ze Zhang, Qingcui Li, Xiao Chang i Xiaoping Liu. "TeCD: The eccDNA Collection Database for extrachromosomal circular DNA". BMC Genomics 24, nr 1 (27.01.2023). http://dx.doi.org/10.1186/s12864-023-09135-5.
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Abstract Background Extrachromosomal circular DNA (eccDNA) is a kind of DNA that widely exists in eukaryotic cells. Studies in recent years have shown that eccDNA is often enriched during tumors and aging, and participates in the development of cell physiological activities in a special way, so people have paid more and more attention to the eccDNA, and it has also become a critical new topic in modern biological research. Description We built a database to collect eccDNA, including animals, plants and fungi, and provide researchers with an eccDNA retrieval platform. The collected eccDNAs were processed in a uniform format and classified according to the species to which it belongs and the chromosome of the source. Each eccDNA record contained sequence length, start and end sites on the corresponding chromosome, order of the bases, genomic elements such as genes and transposons, and other information in the respective sequencing experiment. All the data were stored into the TeCD (The eccDNA Collection Database) and the BLAST (Basic Local Alignment Search Tool) sequence alignment function was also added into the database for analyzing the potential eccDNA sequences. Conclusion We built TeCD, a platform for users to search and obtain eccDNA data, and analyzed the possible potential functions of eccDNA. These findings may provide a basis and direction for researchers to further explore the biological significance of eccDNA in the future.
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Peng, Yue, Yixi Li, Wei Zhang, Yu ShangGuan, Ting Xie, Kang Wang, Jing Qiu i in. "The characteristics of extrachromosomal circular DNA in patients with end-stage renal disease". European Journal of Medical Research 28, nr 1 (27.03.2023). http://dx.doi.org/10.1186/s40001-023-01064-z.
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Abstract Background End-stage renal disease (ESRD) is the final stage of chronic kidney disease (CKD). In addition to the structurally intact chromosome genomic DNA, there is a double-stranded circular DNA called extrachromosomal circular DNA (eccDNA), which is thought to be involved in the epigenetic regulation of human disease. However, the features of eccDNA in ESRD patients are barely known. In this study, we identified eccDNA from ESRD patients and healthy people, as well as revealed the characteristics of eccDNA in patients with ESRD. Methods Using the high-throughput Circle-Sequencing technique, we examined the eccDNA in peripheral blood mononuclear cells (PBMCs) from healthy people (NC) (n = 12) and ESRD patients (n = 16). We analyzed the length distribution, genome elements, and motifs feature of eccDNA in ESRD patients. Then, after identifying the specific eccDNA in ESRD patients, we explored the potential functions of the target genes of the specific eccDNA. Finally, we investigated the probable hub eccDNA using algorithms. Results In total, 14,431 and 11,324 eccDNAs were found in the ESRD and NC groups, respectively, with sizes ranging from 0.01 kb to 60 kb at most. Additionally, the ESRD group had a greater distribution of eccDNA on chromosomes 4, 11, 13, and 20. In two groups, we also discovered several motifs of specific eccDNAs. Furthermore, we identified 13,715 specific eccDNAs in the ESRD group and 10,585 specific eccDNAs in the NC group, both of which were largely annotated as mRNA catalog. Pathway studies using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that the specific eccDNA in ESRD was markedly enriched in cell junction and communication pathways. Furthermore, we identified potentially 20 hub eccDNA-targeting genes from all ESRD-specific eccDNA-targeting genes. Also, we found that 39 eccDNA-targeting genes were associated with ESRD, and some of these eccDNAs may be related to the pathogenesis of ESRD. Conclusions Our findings revealed the characteristics of eccDNA in ESRD patients and discovered potentially hub and ESRD-relevant eccDNA-targeting genes, suggesting a novel probable mechanism of ESRD.
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Wu, Pan, Yuhang Liu, Ruijia Zhou, Lingyun Liu, Hongli Zeng, Fang Xiong, Shanshan Zhang i in. "Extrachromosomal Circular DNA: A New Target in Cancer". Frontiers in Oncology 12 (14.04.2022). http://dx.doi.org/10.3389/fonc.2022.814504.
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Genomic instability and amplification are intrinsically important traits determining the development and heterogeneity of tumors. The role of extrachromosomal circular DNA (eccDNA) in tumors has recently been highlighted. EccDNAs are unique genetic materials located off the chromosomal DNA. They have been detected in a variety of tumors. This review analyzes the mechanisms involved in the formation of eccDNAs and their genetic characteristics. In addition, the high-copy number and transcriptional levels of oncogenes located in eccDNA molecules contribute to the acceleration of tumor evolution and drug resistance and drive the development of genetic heterogeneity. Understanding the specific genomic forms of eccDNAs and characterizing their potential functions will provide new strategies for tumor therapy. Further research may yield new targets and molecular markers for the early diagnosis and treatment of human cancer.
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Zhu, Yi, Zhihui Liu, Yuduo Guo, Shenglun Li, Yanming Qu, Lin Dai, Yujia Chen, Weihai Ning, Hongwei Zhang i Lixin Ma. "Whole-genome sequencing of extrachromosomal circular DNA of cerebrospinal fluid of medulloblastoma". Frontiers in Oncology 12 (8.11.2022). http://dx.doi.org/10.3389/fonc.2022.934159.
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BackgroundMedulloblastoma (MB) is a malignant tumor associated with a poor prognosis in part due to a lack of effective detection methods. Extrachromosomal circular DNA (eccDNA) has been associated with multiple tumors. Nonetheless, little is currently known on eccDNA in MB.MethodsGenomic features of eccDNAs were identified in MB tissues and matched cerebrospinal fluid (CSF) and compared with corresponding normal samples using Circle map. The nucleotides on both sides of the eccDNAs’ breakpoint were analyzed to understand the mechanisms of eccDNA formation. Bioinformatics analysis combined with the Gene Expression Omnibus (GEO) database identified features of eccDNA-related genes in MB. Lasso Cox regression model, univariate and multivariate Cox regression analysis, time-dependent ROC, and Kaplan–Meier curve were used to assess the potential diagnostic and prognostic value of the hub genes.ResultsEccDNA was profiled in matched tumor and CSF samples from MB patients, and control, eccDNA-related genes enriched in MB were identified. The distribution of eccDNAs in the genome was closely related to gene density and the mechanism of eccDNA formation was evaluated. EccDNAs in CSF exhibited similar distribution with matched MB tissues but were differentially expressed between tumor and normal. Ten hub genes prominent in both the eccDNA dataset and the GEO database were selected to classify MB patients to either high- or low-risk groups, and a prognostic nomogram was thus established.ConclusionsThis study provides preliminary evidence of the characteristics and formation mechanism of eccDNAs in MB and CSF. Importantly, eccDNA-associated hub genes in CSF could be used as diagnostic and prognostic biomarkers for MB.
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Wanchai, Visanu, Piroon Jenjaroenpun, Thongpan Leangapichart, Gerard Arrey, Charles M. Burnham, Maria C. Tümmler, Jesus Delgado-Calle, Birgitte Regenberg i Intawat Nookaew. "CReSIL: accurate identification of extrachromosomal circular DNA from long-read sequences". Briefings in Bioinformatics, 4.10.2022. http://dx.doi.org/10.1093/bib/bbac422.
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Abstract Extrachromosomal circular DNA (eccDNA) of chromosomal origin is found in many eukaryotic species and cell types, including cancer, where eccDNAs with oncogenes drive tumorigenesis. Most studies of eccDNA employ short-read sequencing for their identification. However, short-read sequencing cannot resolve the complexity of genomic repeats, which can lead to missing eccDNA products. Long-read sequencing technologies provide an alternative to constructing complete eccDNA maps. We present a software suite, Construction-based Rolling-circle-amplification for eccDNA Sequence Identification and Location (CReSIL), to identify and characterize eccDNA from long-read sequences. CReSIL’s performance in identifying eccDNA, with a minimum F1 score of 0.98, is superior to the other bioinformatic tools based on simulated data. CReSIL provides many useful features for genomic annotation, which can be used to infer eccDNA function and Circos visualization for eccDNA architecture investigation. We demonstrated CReSIL’s capability in several long-read sequencing datasets, including datasets enriched for eccDNA and whole genome datasets from cells containing large eccDNA products. In conclusion, the CReSIL suite software is a versatile tool for investigating complex and simple eccDNA in eukaryotic cells.
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Zhong, Tengwei, Wenqing Wang, Houyan Liu, Maolin Zeng, Xinyu Zhao i Zhiyun Guo. "eccDNA Atlas: a comprehensive resource of eccDNA catalog". Briefings in Bioinformatics, 9.02.2023. http://dx.doi.org/10.1093/bib/bbad037.
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Abstract Extrachromosomal circular DNA (eccDNA) represents a large category of non-mitochondrial and non-plasmid circular extrachromosomal DNA, playing an indispensable role in various aspects such as tumorigenesis, immune responses. However, the information of characteristics and functions about eccDNA is fragmented, hiding behind abundant literatures and massive whole-genome sequencing (WGS) data, which has not been sufficiently used for the identification of eccDNAs. Therefore, establishing an integrated repository portal is essential for identifying and analyzing eccDNAs. Here, we developed eccDNA Atlas (http://lcbb.swjtu.edu.cn/eccDNAatlas), a user-friendly database of eccDNAs that aims to provide a high-quality and integrated resource for browsing, searching and analyzing eccDNAs from multiple species. eccDNA Atlas currently contains 629 987 eccDNAs and 8221 ecDNAs manually curated from literatures and 1105 ecDNAs predicted by AmpliconArchitect based on WGS data involved in 66 diseases, 57 tissues and 319 cell lines. The content of each eccDNA entry includes multiple aspects such as sequence, disease, function, characteristic, validation strategies. Furthermore, abundant annotations and analyzing utilities were provided to explore existing eccDNAs in eccDNA Atlas or user-defined eccDNAs including oncogenes, typical enhancers, super enhancers, CTCF-binding sites, SNPs, chromatin accessibility, eQTLs, gene expression, survival and genome visualization. Overall, eccDNA Atlas provides an integrated eccDNA data warehouse and serves as an important tool for future research.
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Zhou, Lina, Wenyi Tang, Bo Ye i Lingyun Zou. "Characterization, biogenesis model, and current bioinformatics of human extrachromosomal circular DNA". Frontiers in Genetics 15 (29.04.2024). http://dx.doi.org/10.3389/fgene.2024.1385150.
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Human extrachromosomal circular DNA, or eccDNA, has been the topic of extensive investigation in the last decade due to its prominent regulatory role in the development of disorders including cancer. With the rapid advancement of experimental, sequencing and computational technology, millions of eccDNA records are now accessible. Unfortunately, the literature and databases only provide snippets of this information, preventing us from fully understanding eccDNAs. Researchers frequently struggle with the process of selecting algorithms and tools to examine eccDNAs of interest. To explain the underlying formation mechanisms of the five basic classes of eccDNAs, we categorized their characteristics and functions and summarized eight biogenesis theories. Most significantly, we created a clear procedure to help in the selection of suitable techniques and tools and thoroughly examined the most recent experimental and bioinformatics methodologies and data resources for identifying, measuring and analyzing eccDNA sequences. In conclusion, we highlighted the current obstacles and prospective paths for eccDNA research, specifically discussing their probable uses in molecular diagnostics and clinical prediction, with an emphasis on the potential contribution of novel computational strategies.