Investigating cellular heterogeneity at the single-cell level by the flexible and mobile extrachromosomal circular DNA

Extrachromosomal circular DNA (eccDNA) is a special class of DNA derived from linear chromosomes. It coexists independently with linear chromosomes in the nucleus. eccDNA has been identified in multiple organisms, including Homo sapiens, and has been shown to play important roles relevant to tumor pro-gression and drug resistance. To date, computational tools developed for eccDNA detection are only ap-plicable to bulk tissue. Investigating eccDNA at the single-cell level using a computational approach will elucidate the heterogeneous and cell-type-specific landscape of eccDNA within cellular context. Here, we performed the first eccDNA analysis at the single-cell level using data generated by single-cell Assay for Transposase-Accessible Chromatin with sequencing (scATAC-seq) in adult and pediatric glioblastoma (GBM) samples. Glioblastoma multiforme (GBM) is an aggressive tumor of the central nervous system with a poor prognosis. Our analysis provides an overview of cellular origins, genomic distribution, as well as the dif-ferential regulations between linear and circular genome under disease-and cell-type-specific conditions across the open chromatin regions in GBM. We focused on some eccDNA elements that are potential mobile enhancers acting in a trans-regulation manner. In summary, this pilot study revealed novel eccDNA features in the cellular context of brain tumor, supporting the strong need for eccDNA investigation at the single-cell level.(c) 2023 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Automated summary

This article reports the first single-cell level analysis of eccDNA in glioblastoma (GBM) samples. The study revealed the presence of potential mobile enhancers acting in a trans-regulation manner in GBM. This research provides insights into the novel features of eccDNA in the cellular context of brain tumors, highlighting the importance of investigating eccDNA at the single-cell level.