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EccDNA atlas in male mice reveals features protecting genes against transcription-induced eccDNA formation
Xue Liang1,2, Gerard Arrey1, Yating Qin1,2
1Section for Ecology and Evolution, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Abstract:
eccDNA is a driver of many cancers and a potential intermediate in other age-related disorders. However, little is known about the mechanisms underlying eccDNA formation in healthy tissue and how aging affects these processes. Here, we present an atlas of eccDNA across seven tissues of male mice spanning four ages. EccDNA correlates with open chromatin characterized by signatures of H3K27ac and H3K4me1. Additionally, the mutational load of eccDNA on genes correlates with tissue-specific transcription and increases logarithmically as a function of transcript level. Still, a population of intron-dense genes with many splice forms remains sheltered from eccDNA formation. We also find that the total number of eccDNA molecules does not increase as mice age, unlike other types of mutations. Our data reveal a link between eccDNA formation and transcript level that may drive gene architecture in mammals.
Insights
Extrachromosomal circular DNA (eccDNA) formation is linked to gene transcription levels in mammals. Unlike other mutations, eccDNA accumulation does not increase with age in mice.
Area of Science:
- Genomics
- Molecular Biology
- Aging Research
Background:
- Extrachromosomal circular DNA (eccDNA) is implicated in cancer and age-related diseases.
- Mechanisms of eccDNA formation in healthy tissues and during aging remain largely unknown.
Purpose of the Study:
- To investigate eccDNA formation across different tissues and ages in male mice.
- To explore the relationship between eccDNA, chromatin state, and gene transcription.
Main Methods:
- Generated an atlas of eccDNA in seven male mouse tissues across four age groups.
- Analyzed eccDNA correlation with open chromatin marks (H3K27ac, H3K4me1).
- Assessed eccDNA mutational load in relation to gene transcription levels and gene architecture.
Main Results:
- EccDNA formation correlates with open chromatin signatures.
- EccDNA mutational load increases logarithmically with gene transcript levels.
- Intron-dense genes with multiple splice forms are protected from eccDNA formation.
- Total eccDNA molecule count does not increase with age in mice.
Conclusions:
- EccDNA formation is closely linked to gene transcription levels.
- Aging does not increase the overall abundance of eccDNA molecules.
- These findings suggest eccDNA formation influences mammalian gene architecture.
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