Stable intronic sequence RNAs (sisRNAs): a new layer of gene regulation

Abstract

Upon splicing, introns are rapidly degraded. Hence, RNAs derived from introns are commonly deemed as junk sequences. However, the discoveries of intronic-derived small nucleolar RNAs (snoRNAs), small Cajal body associated RNAs (scaRNAs) and microRNAs (miRNAs) suggested otherwise. These non-coding RNAs are shown to play various roles in gene regulation. In this review, we highlight another class of intron-derived RNAs known as stable intronic sequence RNAs (sisRNAs). sisRNAs have been observed since the 1980 s; however, we are only beginning to understand their biological significance. Recent studies have shown or suggested that sisRNAs regulate their own host's gene expression, function as molecular sinks or sponges, and regulate protein translation. We propose that sisRNAs function as an additional layer of gene regulation in the cells.

Keywords: Intron; Non-coding RNA; sisRNA.

Fig. 1

Biogenesis of linear and circular sisRNAs. During splicing, branch point nucleotide adenosine forms a 2′–5′ phosphodiester bond with the 5′ end of the intron, generating a lariat intermediate. The free 3′ OH group of the exon then cleaves the 3′ end of the lariat intermediate and joins the two exons together with a lariat as a by-product. The lariat can either be debranched by a Lariat debranching enzyme into a linear sisRNA or be trimmed at the 3′ end by an exonuclease into a circular sisRNA. Exons and introns are in blue and black, respectively

Fig. 2

sisRNAs regulate host gene expression. a Model of a Drosophila sisRNA, sisR-1, biogenesis and its regulation on its parental gene rga through repression of ASTR. b Model for the regulation of IgH CSR in B cells by the intronic switch RNA, acting as guides to target AID to the IgH locus. c Model of a circular intronic RNA, ci-ankrd52, and its regulatory role on its parental gene expression via interactions with RNA Pol. II

Fig. 3

sisRNAs act as molecular sinks or sponges. a Model of sisRNAs from the PWS region, sno-lncRNAs, sequestering Fox2 proteins and altering Fox2-regulated splicing. b Model of a viral sisRNA, ebv-sisRNA-1, acting as a molecular sink against miR-142-3p, preventing the repression of the EBV lytic gene product

Fig. 4

sisRNAs regulate protein translation. a Linear map of the HSV genome. The 2-kb LAT intron is processed from the primary LAT transcript which is transcribed from the internal repeat long (IR_L) and short (IR_S) regions on the genome. b Model for the regulation of translation of Hsp70 by the 2-kb LAT, ensuring the survival of the host cell during reactivation from latency. U _L unique long, U _S unique short, TR _L terminal repeat long, TR _S terminal repeat short