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PLoS Genet. 2015 Feb 6;11(2):e1005001. doi: 10.1371/journal.pgen.1005001. eCollection 2015 Feb.

Discovery of CTCF-sensitive Cis-spliced fusion RNAs between adjacent genes in human prostate cells.

Author information

1
Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
2
Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America; Pharmacy Department of Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China.
3
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
4
Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America; Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.

Abstract

Genes or their encoded products are not expected to mingle with each other unless in some disease situations. In cancer, a frequent mechanism that can produce gene fusions is chromosomal rearrangement. However, recent discoveries of RNA trans-splicing and cis-splicing between adjacent genes (cis-SAGe) support for other mechanisms in generating fusion RNAs. In our transcriptome analyses of 28 prostate normal and cancer samples, 30% fusion RNAs on average are the transcripts that contain exons belonging to same-strand neighboring genes. These fusion RNAs may be the products of cis-SAGe, which was previously thought to be rare. To validate this finding and to better understand the phenomenon, we used LNCaP, a prostate cell line as a model, and identified 16 additional cis-SAGe events by silencing transcription factor CTCF and paired-end RNA sequencing. About half of the fusions are expressed at a significant level compared to their parental genes. Silencing one of the in-frame fusions resulted in reduced cell motility. Most out-of-frame fusions are likely to function as non-coding RNAs. The majority of the 16 fusions are also detected in other prostate cell lines, as well as in the 14 clinical prostate normal and cancer pairs. By studying the features associated with these fusions, we developed a set of rules: 1) the parental genes are same-strand-neighboring genes; 2) the distance between the genes is within 30kb; 3) the 5' genes are actively transcribing; and 4) the chimeras tend to have the second-to-last exon in the 5' genes joined to the second exon in the 3' genes. We then randomly selected 20 neighboring genes in the genome, and detected four fusion events using these rules in prostate cancer and non-cancerous cells. These results suggest that splicing between neighboring gene transcripts is a rather frequent phenomenon, and it is not a feature unique to cancer cells.

PMID:
25658338
PMCID:
PMC4450057
DOI:
10.1371/journal.pgen.1005001
[Indexed for MEDLINE]
Free PMC Article

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