Abstract
BackgroundRecently, thousands of circular RNAs (circRNAs) have been discovered in various tissues and cell types from human, mouse, fruit fly and nematodes. However, expression of circRNAs across mammalian brain development has never been examined.ResultsHere we profile the expression of circRNA in five brain tissues at up to six time-points during fetal porcine development, constituting the first report of circRNA in the brain development of a large animal. An unbiased analysis reveals a highly complex regulation pattern of thousands of circular RNAs, with a distinct spatio-temporal expression profile. The amount and complexity of circRNA expression was most pronounced in cortex at day 60 of gestation. At this time-point we find 4634 unique circRNAs expressed from 2195 genes out of a total of 13,854 expressed genes. Approximately 20 % of the porcine splice sites involved in circRNA production are functionally conserved between mouse and human. Furthermore, we observe that “hot-spot” genes produce multiple circRNA isoforms, which are often differentially expressed across porcine brain development. A global comparison of porcine circRNAs reveals that introns flanking circularized exons are longer than average and more frequently contain proximal complementary SINEs, which potentially can facilitate base pairing between the flanking introns. Finally, we report the first use of RNase R treatment in combination with in situ hybridization to show dynamic subcellular localization of circRNA during development.ConclusionsThese data demonstrate that circRNAs are highly abundant and dynamically expressed in a spatio-temporal manner in porcine fetal brain, suggesting important functions during mammalian brain development.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0801-3) contains supplementary material, which is available to authorized users.
Highlights
Thousands of circular RNAs have been discovered in various tissues and cell types from human, mouse, fruit fly and nematodes
To investigate potential erroneous circular RNA (circRNA) detection derived from mis-annotation of linear transcripts, we added an extra step to the circRNA annotation pipeline where all candidate circRNA splice junctions were mapped to the porcine genome using the BLAT tool [20]
Junctions that mapped to the genome in a linear manner were deemed as wrongly annotated circRNA
Summary
Thousands of circular RNAs (circRNAs) have been discovered in various tissues and cell types from human, mouse, fruit fly and nematodes. Expression of circRNAs across mammalian brain development has never been examined. The phenomenon of circular RNA (circRNA) has gone from being perceived as a rare curiosity to having a central regulatory role in RNA metabolism [1,2,3,4]. By adding a new layer of complexity to RNA biology, circRNA may be an integral regulatory entity required to develop and maintain multiple distinct mammalian cell types and organs from the same genetic information. We have quantified the spatiotemporal prevalence of circRNA levels during development in the fetal mammalian brain by Illumina deep sequencing of porcine brain samples
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