Abstract
Extrachromosomal DNA exists in two forms: Covalently closed circular and linear. While diverse types of circular extrachromosomal DNA have been identified with validated in vivo functions, little is known about linear extrachromosomal DNA. In this study, we identified small, single-stranded linear extrachromosomal DNAs (SSLmicroDNAs) in the nuclei of mouse hearts, mouse brains, HEK293, and HeLa cells. We used a pull-down system based on the single-stranded DNA binding protein RecAf. We found that SSLmicroDNAs aligned predominantly to intergenic and intragenic regions of the genome, owned a variety of single nucleotide polymorphism sites, and strongly associated with H3K27Ac marks. The regions were tens to hundreds of nucleotides long, periodically separated by AT, TT, or AA dinucleotides. It has been demonstrated that SSLmicroDNAs in the nuclei of normal cells target microRNAs, which regulate biological processes. In summary, our present work identified a new form of extrachromosomal DNAs, which function inside nuclei and interact with microRNAs. This finding provides a possible research field into the function of extrachromosomal DNA.
Highlights
Extrachromosomal DNA—DNA molecules separated from chromosomes—exist in two main forms: Covalently closed circular and linear DNA [1,2,3,4,5]
Our present work identified a new form of extrachromosomal linear DNA, single-stranded linear microDNAs (SSLmicroDNAs), which are found in the nuclei of multiple cell types, including adult mouse hearts, mouse brains, HEK293 cells, and HeLa cells
HEK293SSLmicroDNAs, ~60% of MHSSLmicroDNAs, and ~40% of MBSSLmicroDNAs were conserved between two or more species, whereas only 32.86% of HeLaSSLmicroDNAs shared this feature (Figure 4e,f). These results indicated that SSLmicroDNAs in normal tissues or cells are slightly more conserved compared to their tumor-derived counterparts
Summary
Extrachromosomal DNA—DNA molecules separated from chromosomes—exist in two main forms: Covalently closed circular and linear DNA [1,2,3,4,5]. Mitochondrial DNA are located in mitochondria and represent typical extrachromosomal circular DNA (eccDNA). This type of DNA encodes functional genes and contributes to the nuclear genomes’ instability [6]. Small polydispersed circular DNA, double minute chromosomes, episomes, minichromosomes, autonomously replicating sequences, telomeric-circles, B- and T-cell receptor excision circles, and extrachromosomal elements induced by c-myc oncogene deregulation and resulting in genomic instability were discovered as extrachromosomal circular DNA molecules with unique properties and relevant in vivo functions, which are produced randomly or non-randomly [1,7,8,9,10]. Much attention has focused on a class of small circular extrachromosomal
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