title: Discovery of CTCF-sensitive Cis-spliced fusion RNAs between adjacent genes in human prostate cells.
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.
authors: Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
authors: Fujun
authors: F
authors: Qin
authors: 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.
authors: Zhenguo
authors: Z
authors: Song
authors: Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
authors: Mihaela
authors: M
authors: Babiceanu
authors: Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
authors: Yansu
authors: Y
authors: Song
authors: Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
authors: Loryn
authors: L
authors: Facemire
authors: Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
authors: Ritambhara
authors: R
authors: Singh
authors: Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
authors: Mazhar
authors: M
authors: Adli
authors: 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.
authors: Hui
authors: H
authors: Li
mesh_terms: D001483:Base Sequence; D000076246:CCCTC-Binding Factor; D002459:Cell Fusion; D045744:Cell Line, Tumor; D005091:Exons; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D015894:Genome, Human; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012326:RNA Splicing / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D017423:Sequence Analysis, RNA
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D012097:Repressor Proteins