ciRS-7 exonic sequence is embedded in a long non-coding RNA locus

Cirs-7 is an intensely studied,highly expressed and conserved circrna. essentially nothing is known about its biogenesis,including the location of its promoter. a prevailing assumption has been that cirs-7 is an exceptional circrna because it is transcribed from a locus lacking any mature linear rna transcripts of the same sense. to study the biogenesis of cirs-7,we developed an algorithm to define its promoter and predicted that the human cirs-7 promoter coincides with that of the long non-coding rna,linc00632. we validated this prediction using multiple orthogonal experimental assays. we also used computational approaches and experimental validation to establish that cirs-7 exonic sequence is embedded in linear transcripts that are flanked by cryptic exons in both human and mouse. together,this experimental and computational evidence generates a new model for regulation of this locus: (a) cirs-7 is like other circrnas,as it is spliced into linear transcripts; (b) expression of cirs-7 is primarily determined by the chromatin state of linc00632 promoters; (c) transcription and splicing factors sufficient for cirs-7 biogenesis are expressed in cells that lack detectable cirs-7 expression. these findings have significant implications for the study of the regulation and function of cirs-7,and the analytic framework we developed to jointly analyze rna-seq and chip-seq data reveal the potential for genome-wide discovery of important biological regulation missed in current reference annotations. © 2017 barrett et al.