Regulatory Role of Circular RNAs and Neurological Disorders

Abstract

Circular RNAs (circRNAs) are a class of long noncoding RNAs that are characterized by the presence of covalently linked ends and have been found in all life kingdoms. Exciting studies in regulatory roles of circRNAs are emerging. Here, we summarize classification, characteristics, biogenesis, and regulatory functions of circRNAs. CircRNAs are found to be preferentially expressed along neural genes and in neural tissues. We thus highlight the association of circRNA dysregulation with neurodegenerative diseases such as Alzheimer's disease. Investigation of regulatory role of circRNAs will shed novel light in gene expression mechanisms during development and under disease conditions and may identify circRNAs as new biomarkers for aging and neurodegenerative disorders.

Keywords: Back-splicing; Circular RNA; Neurodegeneration; Regulatory RNA; microRNA sponge.

Figure 1. Three major subclasses of circRNAs

Exonic circRNAs (ecircRNAs) consist of only exon(s) (usually less than five) and represent the most important group of circRNA class. EcircRNAs have cytoplasmatic location and may regulate microRNA and protein functions. Exon-intron circRNAs (EIciRNAs) are composed of at least two exons and one retained intron. EIciRNAs have nuclear localization and have been found to be able to regulate gene transcription in cis and probably also in trans. Intronic circRNAs (ciRNAs) are derived from intron lariats and are accumulated in the nucleus in which regulate gene transcription in cis.

Figure 2. Direct back-splicing model of circRNA formation

CircRNAs are derived from precursor mRNA, and the back-splicing reaction is catalyzed by the spliceosome. Reverse complementary sequence, such as Alu or not Alu elements, and RNA binding proteins (RBPs), such as Quaking I (QKI) and Muscleblind (MBL), might work in a combinatorial manner to bring the splicing sites into close proximity and facilitate back-splicing reaction. Long flanking introns might facilitate back splicing by inducing structural flexibility. Finally, the intervening intron is removed or retained to generate ecircRNA or EIciRNA.

Figure 3. Exon-skipping model of circRNA formation

During exon skipping, a linear mRNA and a skipped exon(s) are formed. The skipped exon(s) then generate a big lariat intermediate, which undergoes internal splicing by inducing the juxtaposition of the putative splice sites and in turn produces ecircRNA or EIciRNA.

Figure 4. Model of intronic circRNA (ciRNA) formation

The process of ciRNA formation depends on a consensus motif near the 5′ splice site that contains 7nt GU-rich motifs and 11nt C-rich element near to the branch point site. Intron are excised during precursor mRNA processing. Intronic circularization requires the release of the 3′ exon, leaving the 2-OH terminal group free. The intron terminal group then attacks the 5′ intron-exon junction, resulting in 2′-5′ loop formation. The consensus motifs asisit escape of debranching induced by the debranching enzyme. The intron lariat is finally cleaved by the exonucleolytic enzyme to form ciRNA.

Figure 5. Mechanism of the role of circular RNA sponge for miRNA-7 (ciRS-7)

(A) ciRS-7 contains over 70 miR-7 target sites and is capable to form a complex with Argonaute (AGO) protein in a miR-7 dependent manner. (B) Target genes of miR-7 is transcribed and silenced by miR-7. ciRS-7, which is localized in the cytoplasm, can function as miR-7 sponge to block miR-7 silencing activity and release miR-7 inhibition to its target genes.