Trends in Neurosciences
ReviewCircular RNAs in Brain and Other Tissues: A Functional Enigma
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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2022, Molecular Therapy OncolyticsCitation Excerpt :circRNAs are frequently found in neural tissue and are expressed differentially in different parts of the brain. This finding may be due to the fact that there are a variety of different protein-coding genes, which produce different circRNAs, splicing factors, and RNA-binding proteins (RBPs), which regulate the formation of circRNAs.26 Piwi-interacting RNAs (piRNAs) are another type of ncRNA that are 26–30 nt in length and bind to Piwi proteins.