Extrachromosomal DNA (ecDNA) molecules associated with transcriptionally active genes on linear chromosomes.

  • Major Finding: Extrachromosomal DNA (ecDNA) molecules associated with transcriptionally active genes on linear chromosomes.

  • Concept: ecDNA molecules are independent circular DNA that may be tens to millions of base pairs long.

  • Impact: ecDNA-induced transcriptional activation may be a means by which ecDNA can promote oncogenesis.

The presence of high levels of extrachromosomal DNA (ecDNA), a type of circular, histone-packaged DNA that is separate from the canonical chromosomes and can range from tens to millions of base pairs in length, is a common feature of cancer cells. Zhu, Gujar, Wong, and colleagues investigated the spatial organization of ecDNA molecules in the nucleus and its potential functional impacts, finding evidence for extensive intra-ecDNA interactions along with interactions between ecDNA molecules and conventional chromatin in cancer cells. ecDNA molecules were more often found to be associated with sites bound by RNA polymerase II on ordinary chromosomes, mostly at or around chromosomal promoter regions, suggesting a possible role in transcriptional regulation. Notably, evaluation of the promoter regions of three oncogenes amplified on cancer cell ecDNAs revealed that these genetic regions preferentially formed contacts with regions of both canonical chromosomes and ecDNA molecules that had high levels of histone 3 lysine residue 27 acetylation (H3K27ac), a marker of active chromatin. Interestingly, ecDNA–linear chromosome contact regions were associated with actively transcribed genes, and further investigation revealed that these contacts were highly specific and may have functioned to connect superenhancer elements to target genes in trans. Experiments using synthetic ecDNA molecules further supported the notion that ecDNA molecules could serve as mobile transcriptional enhancers, increasing transcription of genes at chromosomal locations they bind. Due to observed spatial clustering of actively transcribed oncogenes interacting with these ecDNA molecules, it is possible that, in addition to their known oncogenic role of harboring multiple copies of oncogenes, ecDNA molecules may act epigenetically to enhance transcription of oncogenes in cancer. The previously unexplored concept that ecDNA can function as a mobile trans activator in a cancer-specific manner may have translational value.

Zhu Y, Gujar AD, Wong CH, Tjong H, Ngan CY, Gong L, et al. Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription. Cancer Cell 2021; 39:694–707.E7.

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