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

Yanfen Zhu, Amit D Gujar, Chee-Hong Wong, Harianto Tjong, Chew Yee Ngan, Liang Gong, Yi-An Chen, Hoon Kim, Jihe Liu, Meihong Li, Adam Mil-Homens, Rahul Maurya, Chris Kuhlberg, Fanyue Sun, Eunhee Yi, Ana C deCarvalho, Yijun Ruan, Roel G W Verhaak, Chia-Lin Wei

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)694-707.e7
JournalCancer Cell
Volume39
Issue number5
DOIs
Publication statusPublished - 10 May 2021

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