Trends in Neurosciences
Volume 39, Issue 9, September 2016, Pages 597-604
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Review
Circular RNAs in Brain and Other Tissues: A Functional Enigma

https://doi.org/10.1016/j.tins.2016.06.006Get rights and content

Trends

CircRNAs, formed by back-splicing, have recently re-emerged as a novel class of RNAs with potential regulatory function.

CircRNAs are most abundant in brain tissues and are often derived from genes specific for neuronal and synaptic function.

CircRNA expression is regulated during neuronal development and by synaptic plasticity, suggesting specific neuronal functions.

Circular RNAs (circRNAs) are RNAs with a covalently closed loop structure that have recently regained the attention of biologists. Using deep RNA sequencing (RNA-seq) coupled with novel bioinformatic approaches, genome-wide studies have detected a large number of circRNAs, many of which are abundant, stable, and well conserved during evolution. With few exceptions, the function of most circRNAs remains elusive. Several recent studies have shown that circRNAs are more enriched in neuronal tissues and are often derived from genes specific for neuronal and synaptic function. Moreover, circRNA expression is regulated during neuronal development and by synaptic plasticity, suggesting specific neuronal functions. In this review, we discuss recent advances in the detection, biogenesis, and potential functions of circRNAs, with a particular focus on brain tissues.

Section snippets

CircRNA: A New Class of RNAs with Potential Regulatory Function

Over the past decade, genome research has fueled the discovery of an ever-growing list of novel RNA species. Beyond the classic tRNA, mRNA, and rRNA, there has emerged a striking diversity of additional RNA types, including miRNA, piwi-interacting (pi)RNA, small nucleolar (sno)RNA, small nuclear (sn)RNA, long noncoding (lnc)RNA, and other noncoding RNAs. More recently, in additional to these linear RNAs with distinct 5′ and 3′ ends, a group of circRNAs with covalently closed loop structures has

CircRNA Detection in the Modern Era of RNA-Seq

The global prevalence of circRNAs was underestimated until recently. CircRNAs were inaccessible to commonly used genome-wide RNA profiling techniques because of their closed structure (without free 5′ or 3′ ends) and the difficulty in distinguishing them from their linear RNA isoforms (derived from the same gene locus). From a detection standpoint, the key difference between a circRNA and its linear counterpart is the presence of specific back-splicing junction sequences. Using microarrays, the

CircRNA Biogenesis

CircRNAs are likely formed by back-splicing. Similar to canonical splicing, back-splicing requires both a canonical splicing signal and the canonical spliceosome machinery 34, 37, but is less efficient and largely occurs post-transcriptionally [38]. The biogenesis of circRNAs can be regulated by cis-elements and trans-factors (Figure 1). It has been demonstrated that both cis-elements and trans-factors can promote circRNA biogenesis by bringing the downstream donor and upstream acceptor sites

CircRNA Expression in Brain

So far, thousands of circRNAs have been discovered in eukaryotic cells. Their expression spans a broad dynamic range, from less than one copy to greater than several hundred copies per cell 15, 16, 17, 23. Compared with protein-coding mRNAs, the expression of circRNAs is more skewed towards to the lower end, with most exhibiting low abundance. Although some circRNAs are more ubiquitously expressed, most of them show a complex tissue and/or cell type- and developmental stage-specific expression

Why Are CircRNAs Abundant in Brain?

Given that circRNA biogenesis can be regulated by cis-elements and trans-factors as discussed above, the higher abundance of circRNAs in brain might be attributed to this regulation. Indeed, as indicated above, many host genes that produce circular RNAs are expressed exclusively in brain, but not other tissues. In addition, neuronal genes often have long introns and it is known that circularized exons are more frequently flanked by longer introns 16, 30, 31, 39. Therefore, it is conceivable

Regulation of CircRNA Expression by Neuronal Development and Plasticity

Several studies have shown that circRNA expression is regulated by various aspects of neuronal development. For example, the differentiation of neurons from cultured undifferentiated cells was associated with enhanced expression of a large population of circRNAs, while a smaller population exhibited decreased expression 26, 38. An analysis of circRNA expression in developing cultured hippocampal neurons (days E18, P1, P10, and P30) revealed a rather abrupt increase in circRNA levels at the

CircRNA Function(s)

Several lines of evidence suggest that circRNAs have important regulatory functions. First, although most circRNAs are of low abundance, a significant population (10–100 or so, depending on the cell type) is expressed at a reasonable level; in many cases, the abundance of the circRNA exceeds that of the associated linear RNA isoform 14, 15, 16, 23, 26, 27. Second, the expression of circRNAs is often regulated in a cell type- and stage-specific manner [17]. As mentioned above, several studies

CircRNA Stability: A Clue to Function?

Compared with linear RNAs, circRNAs are more stable, likely due to their resistance to RNA exonucleases 15, 16, 20. This high stability suggests that the apparent concentration of many circRNAs is dominated by their slow turnover rather than by their production [38]. Therefore, in quiescent and postmitotic cells, such as neurons, circRNAs could accumulate, resulting in higher concentrations than the linear RNAs even though the relative rate of their production remains constant. This fits with

Concluding Remarks

CircRNAs have recently regained attention as noncoding RNA molecules with a potential regulatory function. CircRNAs are highly abundant in brain and are often derived from genes specific for neuronal and synaptic function. CircRNA expression is regulated during neuronal development and by synaptic plasticity, and often such regulation is independent of that of the host linear transcripts. With few exceptions, the function of most circRNAs remains elusive and, as a heterogeneous group, they

Acknowledgments

We thank members of the Chen and Schuman labs for data, analyses, and discussion. We specifically thank Mantian Wang for Figure 1, Figure 2.

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