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Proc Natl Acad Sci U S A. 2019 Feb 4. pii: 201819788. doi: 10.1073/pnas.1819788116. [Epub ahead of print]

Genome-wide colocalization of RNA-DNA interactions and fusion RNA pairs.

Yan Z1,2, Huang N1,2, Wu W1,2, Chen W1,2, Jiang Y1,2, Chen J1,2, Huang X3, Wen X1,2, Xu J4, Jin Q4, Zhang K5, Chen Z6, Chien S7,2,8, Zhong S7,2.

Author information

1
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
2
Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093.
3
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
4
Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, PA 17033.
5
Department of Ophthalmology, University of California, San Diego, La Jolla, CA 92093.
6
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA 91010.
7
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093; shuchien@ucsd.edu szhong@ucsd.edu.
8
Department of Medicine, University of California, San Diego, La Jolla, CA 92093.

Abstract

Fusion transcripts are used as biomarkers in companion diagnoses. Although more than 15,000 fusion RNAs have been identified from diverse cancer types, few common features have been reported. Here, we compared 16,410 fusion transcripts detected in cancer (from a published cohort of 9,966 tumor samples of 33 cancer types) with genome-wide RNA-DNA interactions mapped in two normal, noncancerous cell types [using iMARGI, an enhanced version of the mapping of RNA-genome interactions (MARGI) assay]. Among the top 10 most significant RNA-DNA interactions in normal cells, 5 colocalized with the gene pairs that formed fusion RNAs in cancer. Furthermore, throughout the genome, the frequency of a gene pair to exhibit RNA-DNA interactions is positively correlated with the probability of this gene pair to present documented fusion transcripts in cancer. To test whether RNA-DNA interactions in normal cells are predictive of fusion RNAs, we analyzed these in a validation cohort of 96 lung cancer samples using RNA sequencing (RNA-seq). Thirty-seven of 42 fusion transcripts in the validation cohort were found to exhibit RNA-DNA interactions in normal cells. Finally, by combining RNA-seq, single-molecule RNA FISH, and DNA FISH, we detected a cancer sample with EML4-ALK fusion RNA without forming the EML4-ALK fusion gene. Collectively, these data suggest an RNA-poise model, where spatial proximity of RNA and DNA could poise for the creation of fusion transcripts.

KEYWORDS:

RNA-poise model; RNA–DNA interactions; fusion transcripts

PMID:
30718424
DOI:
10.1073/pnas.1819788116
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Conflict of interest statement

Conflict of interest statement: S.Z. is a cofounder of Genemo, Inc.

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