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EccDNA biogenesis and its role in innate immunity

ABSTRACT: Extrachromosomal circular DNA elements (EccDNAs) have been described in the literature for several decades and are known for their wide existence across species as well as their high heterogeneity in genomic origins. Due to their scarcity and lack of validation tools, their biogenesis as well as their functions are largely unknown. Here, by using a newly developed circular DNA enrichment method, we purified eccDNAs from different cells and mapped their genomic location using both Illumine and Nanopore sequencing. We found that eccDNAs are mapped to genome in a largely random fashion, suggesting a biogenesis mechanism of random ligation of genomic DNA fragments. Consistently, we found that apoptosis inducers can increase the eccDNA generation, which is dependent on DNase 1/3 and DNA ligase 3. Importantly, we demonstrate that eccDNAs function as potent innate immunostimulants in a sequence-independent, but circularization-dependent fashion.

ORGANISM(S): Mus musculus

PROVIDER: GSE165919 | GEO | 2021/08/05

REPOSITORIES: GEO

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Extrachromosomal circular SUZ12 amplicon dictates retinoblastoma progression through reprogramming H3K27 methylation [RNA-seq]

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Extrachromosomal circular SUZ12 amplicon dictates retinoblastoma progression through reprogramming H3K27 methylation [CUT&Tag]

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Whole-genome sequencing of Extrachromosomal circular DNA (eccDNA) of cerebrospinal fluid of Medulloblastoma

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Project description:To explore the presence of extrachromosomal circular DNA (eccDNA) in the anterior capsule of the lens in the eyes of patients with cataract and with high myopia. Circle-Seq was performed to identify differences in the eccDNA and gene expression between the anterior capsule of the lens of patients with simple nuclear cataract (C, n = 6) and patients with nuclear cataract along with high myopia (HM, n = 6). The expression of eccDNA was confirmed using routine quantitative polymerase chain reaction. The eccDNA ranked in C and HM ranged in length from 0.017 kb – 9.9 Mb with two distinctive peaks detected at 0.2 kb and 0.5 kb, while eccDNA that were differentially expressed (up- and down-regulated) ranged in size from 0.05 kb – 57.8 kb with two distinctive peaks observed at 0.1 kb and 0.5 kb. Only 2.5 % of the eccDNA in C and 2 % in HM were > 25 kb in size. The gene-rich chromosomes contributed to more number of eccDNA/Mb, while several well-known high myopia candidate genes, including catenin delta 2 (CTNND2), ubiquitin-like with PHD and ring finger domains 1 binding protein 1 like (UHRF1BP1L) , exhibited significantly increased levels of eccDNA in the anterior capsule of the lens in patients with high myopia. This study highlighted the topologic analysis of the anterior capsule of eyes with high myopia, which is an emerging direction for research and clinical applications. These findings suggested that eccDNA was commonly detected in eyes with high myopia and cataracts, and the candidate genes for high myopia identified in previous studies were also observed in the eccDNA.

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Project description:Interest in extrachromosomal circular DNA (eccDNA) molecules has increased recently because of their widespread presence in normal cells across every species ranging from yeast to humans, their increased levels in cancer cells, and their overlap with oncogenic and drug-resistant genes. However, the majority of eccDNA are too small to carry protein coding genes and their function has remained unknown. We have tested functional capabilities of small eccDNA molecules, termed microDNA, by creating artificial microDNA molecules mimicking known microDNA sequences and have discovered that microDNA express functional small regulatory RNA including microRNA and novel si-like RNA. MicroDNA is transcribed in vitro and in vivo independent of a promoter sequence. MicroDNA which carry miRNA genes form transcripts which are processed into mature miRNA molecules, through the endogenous RNA-interference pathway, which repress a luciferase reporter gene as well as endogenous mRNA targets of the miRNA. Further, microDNA containing sequences of exons repress the endogenous gene from which the microDNA was derived through the formation of novel si-like RNA. We also show that endogenous microDNA associate with RNA polymerases subunits POLR2H and POLR3F. Together, these results suggest that microDNA actively modulate gene expression through the production of both known and novel regulatory small RNA.

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