Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription.
Cancer Cell 2021 May 10; 39(5):694-707.e7
DK107967, HG009409, CA034196, GM127531, CA236681
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.
Zhu, Yanfen; Gujar, Amit D; Wong, Chee-Hong; Tjong, Harianto; Ngan, Chew Yee; Gong, Liang; Chen, Yi-An; Kim, Hoon; Liu, Jihe; Li, Meihong; Mil-Homens, Adam; Maurya, Rahul; Kuhlberg, Chris; Sun, Fanyue; Yi, Eunhee; deCarvalho, Ana C; Ruan, Yijun; Verhaak, Roel G W; and Wei, Chia-Lin, "Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription." (2021). Faculty Research 2021. 101.