Specific expression and functions of circular RNAs

Abstract

In recent years, circular RNAs (circRNAs), a new class of RNA molecules characterized by their covalently closed circular structure, have become a new research paradigm in RNA biology. Many circRNAs are conserved among eukaryotes, localize in specific subcellular compartments, and play different biological roles. Accumulating evidence shows that circRNAs regulate a diversity of cellular processes by acting as miRNA sponges, anchors for circRNA binding proteins (cRBPs), transcriptional regulators, molecular scaffolds, and sources for translation of small proteins/peptides. The emergence of the biological functions of circRNAs has brought a new perspective to our understanding of cellular physiology and disease pathogenesis. Recent studies have shown that the expression of circRNAs is tissue- and cell type-specific and specifically regulated through development or disease progression, where they exert specific biological functions. However, the mechanisms underlying these remain largely unknown. A deeper understanding of how the specific expression of circRNAs is regulated to exert specific biological functions will enable the use of circRNA as a biomarker in clinical practice and the development of new therapeutic approaches. This review aims to summarize recent developments in circRNA biogenesis, functions, and molecular mechanisms. We also provide some specific circRNAs as examples to show their tissue-specific distribution and evaluate the possibility of applying circRNA technologies in molecular research and therapeutics.

Fig. 1. Biogenesis and functional mechanisms of circRNAs.

a Linear mRNA is derived by the conventional splicing process. b Intron pairing model of circRNAs biogenesis; The 3’ splicing donor site in the exon combines with the 5’ splicing acceptor site in the upstream intron that forms a circRNA or ecircRNA by removing the introns between the exons. c Intron pairing-driven circularization; reverse complementary sequences (Alu sequences) direct insertion and generate an EIciRNA or ecircRNA through intron removed or retained. d RBP-induced cyclization: RBPs assist the back-splicing event, in which the introns are removed to form circRNA. e ciRNA formation; ciRNAs are derived from lariat introns. f circRNAs can serve as miRNA sponge. g circRNAs can interact with cRBPs and alter the functions of the proteins. h circRNAs can encode peptides and proteins. i ciRNAs can directly interact with transcription complexes and thus regulate parental gene expression at the transcriptional and translational levels.

Fig. 2. Physiological and pathological functions of circRNAs.

CircRNAs have been reported to play important roles in regulating tissue development, cell proliferation, innate immunity, autophagy, and neuronal functions under physiological conditions. CircRNAs are also involved in the onset and progression of diseases, including cancers, cardiovascular diseases, metabolic diseases, inflammation, and neurodegenerative diseases.

Fig. 3. Tissue- and development-specific of circRNA expression.

The diagram shows the circRNAs that have been reported in various tissues. The red font indicates downregulated circRNAs, while the black font shows upregulated circRNAs in the diseases of specific organs.

Fig. 4. Examples of circRNAs with tissue- or stage-specific expression.

The most studied, highly abundant circRNAs are demonstrated to be expressed tissue-specifically or developmental stage-specifically. Their expression in different organs, functions, and mechanisms are listed. Red lines: microRNA sponge. Blue lines: protein interaction. Green line: transcriptional regulation. Yellow line: translation.