PT  - JOURNAL ARTICLE
AU  - Steven P. Barrett
AU  - Kevin R. Parker
AU  - Caroline Horn
AU  - Miguel Mata
AU  - Julia Salzman
TI  - ciRS-7 exonic sequence is embedded in a long-noncoding RNA locus
AID  - 10.1101/169508
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 169508
4099  - http://biorxiv.org/content/early/2017/07/28/169508.short
4100  - http://biorxiv.org/content/early/2017/07/28/169508.full
AB  - Despite thorough analysis, the human transcriptome is incompletely annotated: some genes lack accurate transcriptional start sites and in some genes, splicing events have been missed. In this paper, we report a significant example of this incompleteness in both the promoter and splicing of ciRS-7, a highly expressed circRNA thought to be exceptional because it is transcribed from a locus lacking any mature linear RNA transcripts of the same sense. Using unbiased computational approaches, we have discovered that the human ciRS-7 exonic sequence is spliced into linear transcripts. Further, we use statistical approaches to discover that its promoter coincides with that of the long non-coding RNA, LINC00632. We validate this prediction using multiple experimental assays and show that the splicing of ciRS-7 into linear transcripts is conserved to mouse. Together, experimental and computational evidence argue that expression of ciRS-7 is primarily determined by epigenetic state of LINC00632 promoters and that transcription and splicing factors sufficient for ciRS-7 biogenesis are expressed in cells that lack detectable ciRS-7 expression. This unbiased joint analysis of RNA-seq and epigenetic data reveal the potential for discovering important biological regulation missed in current reference annotations. Here, we focus on the significant biological implications for the most intensely-studied circular RNA, ciRS-7.