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

doi:10.1016/j.ccell.2021.03.006

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 journal › Article › peer-review

200 Scopus citations

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 language	English
Pages (from-to)	694-707.e7
Journal	Cancer Cell
Volume	39
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2021.03.006
State	Published - 10 May 2021
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ChIA-Drop
ChIA-PET
chromatin interactions
ecDNA
mobile enhancers

Access to Document

10.1016/j.ccell.2021.03.006

Cite this

Zhu, Y., Gujar, A. D., Wong, C. H., Tjong, H., Ngan, C. Y., Gong, L., Chen, Y. A., Kim, H., Liu, J., Li, M., Mil-Homens, A., Maurya, R., Kuhlberg, C., Sun, F., Yi, E., deCarvalho, A. C., Ruan, Y., Verhaak, R. G. W., & Wei, C. L. (2021). Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription. Cancer Cell, 39(5), 694-707.e7. https://doi.org/10.1016/j.ccell.2021.03.006

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title = "Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription",

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.",

keywords = "ChIA-Drop, ChIA-PET, chromatin interactions, ecDNA, mobile enhancers",

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

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = may,

day = "10",

doi = "10.1016/j.ccell.2021.03.006",

language = "English",

volume = "39",

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Zhu, Y, Gujar, AD, Wong, CH, Tjong, H, Ngan, CY, Gong, L, Chen, YA, Kim, H, Liu, J, Li, M, Mil-Homens, A, Maurya, R, Kuhlberg, C, Sun, F, Yi, E, deCarvalho, AC, Ruan, Y, Verhaak, RGW & Wei, CL 2021, 'Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription', Cancer Cell, vol. 39, no. 5, pp. 694-707.e7. https://doi.org/10.1016/j.ccell.2021.03.006

TY - JOUR

T1 - Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription

AU - Zhu, Yanfen

AU - Gujar, Amit D.

AU - Wong, Chee Hong

AU - Tjong, Harianto

AU - Ngan, Chew Yee

AU - Gong, Liang

AU - Chen, Yi An

AU - Kim, Hoon

AU - Liu, Jihe

AU - Li, Meihong

AU - Mil-Homens, Adam

AU - Maurya, Rahul

AU - Kuhlberg, Chris

AU - Sun, Fanyue

AU - Yi, Eunhee

AU - deCarvalho, Ana C.

AU - Ruan, Yijun

AU - Verhaak, Roel G.W.

AU - Wei, Chia Lin

PY - 2021/5/10

Y1 - 2021/5/10

N2 - 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.

AB - 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.

KW - ChIA-Drop

KW - ChIA-PET

KW - chromatin interactions

KW - ecDNA

KW - mobile enhancers

UR - https://www.scopus.com/pages/publications/85105022652

U2 - 10.1016/j.ccell.2021.03.006

DO - 10.1016/j.ccell.2021.03.006

M3 - Article

C2 - 33836152

AN - SCOPUS:85105022652

SN - 1535-6108

VL - 39

SP - 694-707.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

UN SDGs

Keywords

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