Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription.

Document Type

Article

Publication Date

5-10-2021

Publication Title

Cancer cell

Keywords

JGM

JAX Source

Cancer Cell 2021 May 10; 39(5):694-707.e7

Volume

39

Issue

5

First Page

694

Last Page

707

ISSN

1878-3686

PMID

33836152

DOI

https://doi.org/10.1016/j.ccell.2021.03.006

Grant

DK107967, HG009409, CA034196, GM127531, CA236681

Abstract

Extrachromosomal, circular DNA (ecDNA) is emerging as a prevalent yet less characterized oncogenic alteration in cancer genomes. We leverage ChIA-PET and ChIA-Drop chromatin interaction assays to characterize genome-wide ecDNA-mediated chromatin contacts that impact transcriptional programs in cancers. ecDNAs in glioblastoma patient-derived neurosphere and prostate cancer cell cultures are marked by widespread intra-ecDNA and genome-wide chromosomal interactions. ecDNA-chromatin contact foci are characterized by broad and high-level H3K27ac signals converging predominantly on chromosomal genes of increased expression levels. Prostate cancer cells harboring synthetic ecDNA circles composed of characterized enhancers result in the genome-wide activation of chromosomal gene transcription. Deciphering the chromosomal targets of ecDNAs at single-molecule resolution reveals an association with actively expressed oncogenes spatially clustered within ecDNA-directed interaction networks. Our results suggest that ecDNA can function as mobile transcriptional enhancers to promote tumor progression and manifest a potential synthetic aneuploidy mechanism of transcription control in cancer.

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