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Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues.

ABSTRACT: We have identified tens of thousands of short extrachromosomal circular DNAs (microDNA) in mouse tissues as well as mouse and human cell lines. These microDNAs are 200 to 400 base pairs long, are derived from unique nonrepetitive sequence, and are enriched in the 5'-untranslated regions of genes, exons, and CpG islands. Chromosomal loci that are enriched sources of microDNA in the adult brain are somatically mosaic for microdeletions that appear to arise from the excision of microDNAs. Germline microdeletions identified by the "Thousand Genomes" project may also arise from the excision of microDNAs in the germline lineage. We have thus identified a previously unknown DNA entity in mammalian cells and provide evidence that their generation leaves behind deletions in different genomic loci.

SUBMITTER: Shibata Y

PROVIDER: S-EPMC3703515 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues.

Shibata Yoshiyuki Y Kumar Pankaj P Layer Ryan R Willcox Smaranda S Gagan Jeffrey R JR Griffith Jack D JD Dutta Anindya A

Science (New York, N.Y.) 20120308 6077

We have identified tens of thousands of short extrachromosomal circular DNAs (microDNA) in mouse tissues as well as mouse and human cell lines. These microDNAs are 200 to 400 base pairs long, are derived from unique nonrepetitive sequence, and are enriched in the 5'-untranslated regions of genes, exons, and CpG islands. Chromosomal loci that are enriched sources of microDNA in the adult brain are somatically mosaic for microdeletions that appear to arise from the excision of microDNAs. Germline ...[more]

PMID: 22403181

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Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues

Project description:We have identified tens of thousands of short extrachromosomal circular DNAs (microDNA) in mouse tissues as well as mouse and human cell lines. These microDNAs are 200-400 bp long, derived from unique non-repetitive sequence and are enriched in the 5' untranslated regions of genes, exons and CpG islands. Chromosomal loci that are enriched sources of microDNA in adult brain are somatically mosaic for micro-deletions that appear to arise from the excision of microDNAs. Germline microdeletions identified by the "Thousand Genomes" project may also arise from the excision of microDNAs in the germline lineage. We have thus identified a new DNA entity in mammalian cells and provide evidence that their generation leaves behind deletions in different genomic loci.

2012-02-27 | GSE36088 | GEO

Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues

2012-02-27 | E-GEOD-36088 | biostudies-arrayexpress

Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues

Project description:Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues

| PRJNA151905 | ENA

Normal and Cancerous Tissues Release Extrachromosomal Circular DNA (eccDNA) into the Circulation.

Project description:Cell-free circulating linear DNA is being explored for noninvasive diagnosis and management of tumors and fetuses, the so-called liquid biopsy. Previously, we observed the presence of small extrachromosomal circular DNA (eccDNA), called microDNA, in the nuclei of mammalian tissues and cell lines. Now, we demonstrate that cell-free microDNA derived from uniquely mapping regions of the genome is detectable in plasma and serum from both mice and humans and that they are significantly longer (30%-60% >250 bases) than cell-free circulating linear DNA (?150 bases). Tumor-derived human microDNA is detected in the mouse circulation in a mouse xenograft model of human ovarian cancer. Comparing the microDNA from paired tumor and normal lung tissue specimens reveals that the tumors contain longer microDNA. Consistent with human cancers releasing microDNA into the circulation, serum and plasma samples (12 lung and 11 ovarian cancer) collected prior to surgery are enriched for longer cell-free microDNA compared with samples from the same patient obtained several weeks after surgical resection of the tumor. Thus, circular DNA in the circulation is a previously unexplored pool of nucleic acids that could complement miRNAs and linear DNA for diagnosis and for intercellular communication.Implications: eccDNA derived from chromosomal genomic sequence, first discovered in the nuclei of cells, are detected in the circulation, are longer than linear cell-free DNA, and are released from normal tissue and tumors into the circulation. Mol Cancer Res; 15(9); 1197-205. ©2017 AACR.

| S-EPMC5581709 | biostudies-literature

Epigenetic Repeat-Induced Gene Silencing in the Chromosomal and Extrachromosomal Contexts in Human Cells.

Project description:A plasmid bearing both a replication initiation region and a matrix attachment region is spontaneously amplified in transfected mammalian cells and generates plasmid repeats in the extrachromosomal double minutes (DMs) or the chromosomal homogeneously staining region (HSR). Generally, the repeat sequences are subject to repeat-induced gene silencing, the mechanism of which remains to be elucidated. Previous research showed that gene expression from the same plasmid repeat was higher from repeats located at DMs than at the HSR, which may reflect the extrachromosomal environment of the DMs. In the current study, plasmid repeats in both DMs and HSR were associated with repressive histone modifications (H3K9me3, H3K9me2), and the levels of repressive chromatin markers were higher in HSR than in DMs. Inactive chromatin is known to spread to neighboring regions in chromosome arm. Here, we found that such spreading also occurs in extrachromosomal DMs. Higher levels of active histone modifications (H3K9Ac, H3K4me3, and H3K79me2) were detected at plasmid repeats in DMs than in HSR. The level of DNA CpG methylation was generally low in both DMs and HSR; however, there were some hypermethylated copies within the population of repeated sequences, and the frequency of such copies was higher in DMs than in HSR. Together, these data suggest a "DNA methylation-core and chromatin-spread" model for repeat-induced gene silencing. The unique histone modifications at the extrachromosomal context are discussed with regard to the model.

| S-EPMC4985131 | biostudies-literature

Analysis of testicular transcriptome changes in the presence of Y-chromosomal microdeletions

Project description:We investigated the transcriptional changes in human testis in the presence of AZFc/AZFb+c microdeletions. As one encounters a dominating 'germ cell effect' in this pursuit, testicular biopsies were pre-selected by clustering based on similar quantitative germ cell composition. Statistical testing was employed to filter genes that are influenced by the 'deletion effect' using the selected subset of biopsies, thereby obtaining several hundered genes that may be involved in YCMD-induced spermatogenic impairment.

2010-05-01 | GSE21613 | GEO

A Maternally Inherited Rare Case with Chromoanagenesis-Related Complex Chromosomal Rearrangements and De Novo Microdeletions.

Project description:Chromoanagenesis is a phenomenon of highly complex rearrangements involving the massive genomic shattering and reconstitution of chromosomes that has had a great impact on cancer biology and congenital anomalies. Complex chromosomal rearrangements (CCRs) are structural alterations involving three or more chromosomal breakpoints between at least two chromosomes. Here, we present a 3-year-old boy exhibiting multiple congenital malformations and developmental delay. The cytogenetic analysis found a highly complex CCR inherited from the mother involving four chromosomes and five breakpoints due to forming four derivative chromosomes (2, 3, 6 and 11). FISH analysis identified an ultrarare derivative chromosome 11 containing three parts that connected the 11q telomere to partial 6q and 3q fragments. We postulate that this derivative chromosome 11 is associated with chromoanagenesis-like phenomena by which DNA repair can result in a cooccurrence of inter-chromosomal translocations. Additionally, chromosome microarray studies revealed that the child has one subtle maternal-inherited deletion at 6p12.1 and two de novo deletions at 6q14.1 and 6q16.1~6q16.3. Here, we present a familial CCR case with rare rearranged chromosomal structures and the use of multiple molecular techniques to delineate these genomic alterations. We suggest that chromoanagenesis may be a possible mechanism involved in the repair and reconstitution of these rearrangements with evidence for increasing genomic imbalances such as additional deletions in this case.

| S-EPMC9406357 | biostudies-literature

Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma.

Project description:To understand how genomic heterogeneity of glioblastoma (GBM) contributes to poor therapy response, we performed DNA and RNA sequencing on GBM samples and the neurospheres and orthotopic xenograft models derived from them. We used the resulting dataset to show that somatic driver alterations including single-nucleotide variants, focal DNA alterations and oncogene amplification on extrachromosomal DNA (ecDNA) elements were in majority propagated from tumor to model systems. In several instances, ecDNAs and chromosomal alterations demonstrated divergent inheritance patterns and clonal selection dynamics during cell culture and xenografting. We infer that ecDNA was unevenly inherited by offspring cells, a characteristic that affects the oncogenic potential of cells with more or fewer ecDNAs. Longitudinal patient tumor profiling found that oncogenic ecDNAs are frequently retained throughout the course of disease. Our analysis shows that extrachromosomal elements allow rapid increase of genomic heterogeneity during GBM evolution, independently of chromosomal DNA alterations.

| S-EPMC5934307 | biostudies-literature

Amplification of a plasmid bearing a mammalian replication initiation region in chromosomal and extrachromosomal contexts.

Project description:Amplified genes in cancer cells reside on extrachromosomal double minutes (DMs) or chromosomal homogeneously staining regions (HSRs). We used a plasmid bearing a mammalian replication initiation region to model gene amplification. Recombination junctions in the amplified region were comprehensively identified and sequenced. The junctions consisted of truncated direct repeats (type 1) or inverted repeats (type 2) with or without spacing. All of these junctions were frequently detected in HSRs, whereas there were few type 1 or a unique type 2 flanked by a short inverted repeat in DMs. The junction sequences suggested a model in which the inverted repeats were generated by sister chromatid fusion. We were consistently able to detect anaphase chromatin bridges connected by the plasmid repeat, which were severed in the middle during mitosis. De novo HSR generation was observed in live cells, and each HSR was lengthened more rapidly than expected from the classical breakage/fusion/bridge model. Importantly, we found massive DNA synthesis at the broken anaphase bridge during the G1 to S phase, which could explain the rapid lengthening of the HSR. This mechanism may not operate in acentric DMs, where most of the junctions are eliminated and only those junctions produced through stable intermediates remain.

| S-EPMC3035466 | biostudies-literature

Genome-Wide Extrachromosomal Circular DNA Profiling of Paired Hepatocellular Carcinoma and Adjacent Liver Tissues.

Project description: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.

| S-EPMC10670553 | biostudies-literature

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