Exon-intron circular RNAs regulate transcription in the nucleus

Abstract

Noncoding RNAs (ncRNAs) have numerous roles in development and disease, and one of the prominent roles is to regulate gene expression. A vast number of circular RNAs (circRNAs) have been identified, and some have been shown to function as microRNA sponges in animal cells. Here, we report a class of circRNAs associated with RNA polymerase II in human cells. In these circRNAs, exons are circularized with introns 'retained' between exons; we term them exon-intron circRNAs or EIciRNAs. EIciRNAs predominantly localize in the nucleus, interact with U1 snRNP and promote transcription of their parental genes. Our findings reveal a new role for circRNAs in regulating gene expression in the nucleus, in which EIciRNAs enhance the expression of their parental genes in cis, and highlight a regulatory strategy for transcriptional control via specific RNA-RNA interaction between U1 snRNA and EIciRNAs.

Inducible RasGEF1B circular RNA is a positive regulator of ICAM-1 in the TLR4/LPS pathway

“…A recent study suggested that a subclass of circRNAs, exon-intron circRNAs (EIciRNAs), interact with the U1 snRNP and promote the transcription of their parental genes. 13 Despite the progress made so far, the number of functionally characterized circRNAs remains very low. Thousands of cytoplasmic circRNAs have been identified, with most of them having only 1 or 2 binding sites for a particular miRNA, which limits their potential regulatory potency as miRNA "sponges".…”

In vitro circularization of RNA

“…This view has however dramatically changed due to the fact that with the development of deep sequencing and bioinformatic tools a large number of circRNAs have been discovered in mammalian and other cells. [1][2][3][4][5]7 Strikingly, often circRNA is even the more abundant isoform than mRNA. 2,12,13 Due to their covalently closed ring structure, circRNAs have a higher stability in the cellular environment as compared with their linear counterparts, implying that possible functions of circRNA may be associated with the longer life time of these molecules.…”

“…9 Furthermore, circRNAs can be formed from introns (hence termed circular intronic RNA (ciRNA), 6 or from exons with introns retained between the exons (termed exon-intron circRNA (IEciRNA). 7 However, the vast majority of circRNAs apparently is transcribed and spliced from exons of protein and noncoding genes. 1,10,11 Initially discovered as ubiquitous molecules in mice and human cells, those circRNAs were subsequently found as abundant, conserved and stable species in all eukaryotes studied today.…”

“…In fact, based on recent research in the field, circRNAs have been suggested to act as miRNA and protein sponges, to be involved in the modulation of gene expression and splicing, and to be associated with diseases initiation and progression. 4,7,[14][15][16][17][18] Thus, circRNAs have also been considered as biomarkers for diseases prognostics and diagnostics and as targets or tools for disease treatment. [19][20][21] The field of investigations into circRNA and in particular into their putative function within the complex network of regulation of gene expression and splicing is currently very active.…”

“…CircRNAs are found in all kingdoms of life; thousands have been identified across species from Archaea to humans. [1][2][3][4][5][6][7][8] CircRNAs have been known for a long time in form of genomes of viroidal plant pathogenes or Hepatitis delta virus. 9 Furthermore, circRNAs can be formed from introns (hence termed circular intronic RNA (ciRNA), 6 or from exons with introns retained between the exons (termed exon-intron circRNA (IEciRNA).…”