Having an intricate understanding of gene regulation is the underlying key of molecular and cell biology. For many years we have been taught that DNA is double-stranded and RNA is single-stranded, but more recently, new scientific evidence is challenging those traditional notions. Scientists have encountered many cases of RNA forming a double-stranded—or secondary—structure that plays a vital role in the functioning of RNA molecules. Now, a team of Russian scientists have uncovered the role of double-stranded fragments of maturing RNA and showed that the interaction between distant parts of the RNA could regulate gene expression. Findings from the new study were published recently in Nature Communications through an article titled, “Conserved long-range base pairings are associated with pre-mRNA processing of human genes.”

“The ability of nucleic acids to form double-stranded structures is essential for all living systems on Earth,” the authors wrote. “Current knowledge on functional RNA structures is focused on locally occurring base pairs. However, crosslinking and proximity ligation experiments demonstrated that long-range RNA structures are highly abundant.”

These structures are involved in regulating gene expression, where the double-stranded regions typically carry specific functions and, if lost, may cause severe disorders. Sticky complementary regions create a double-stranded structure. For the strands to stick to each other, U and G should appear opposite A and C, respectively. The majority of the sticking regions are located close to one another, but the role of those located far apart has not been well understood.

“We present the most complete to-date catalog of conserved complementary regions (PCCRs) in human protein-coding genes,” the authors noted. “PCCRs tend to occur within introns, suppress intervening exons, and obstruct cryptic and inactive splice sites. The double-stranded structure of PCCRs is supported by decreased icSHAPE nucleotide accessibility, high abundance of RNA editing sites, and frequent occurrence of forked eCLIP peaks. Introns with PCCRs show a distinct splicing pattern in response to RNAPII slowdown, suggesting that splicing is widely affected by co-transcriptional RNA folding.”

Scientists from the Skoltech Center for Life Sciences (CLS), led by Dmitri Pervouchine, PhD, professor, and their colleagues from Russian and international laboratories used molecular and bioinformatics techniques to analyze the structure and roles of complementary RNA regions spaced far apart but capable of forming secondary structures. It transpired that the secondary structure plays an important role in the maturation of information-carrying RNA molecules and particularly in splicing, a process in which noncoding regions are cut out and the coding regions are stitched together. The team showed that the RNA secondary structures could regulate splicing and thus contribute strongly to gene regulation.

“This paper culminates years of research on the RNA secondary structure and its role in the regulation of gene expression. We have published an extensive computation-based catalog of potentially important RNA structures, but the experimental research in this direction is just starting,” commented Pervouchine.

“The enrichment of 3’-ends within PCCRs raises the intriguing hypothesis that coupling between RNA folding and splicing could mediate co-transcriptional suppression of premature pre-mRNA cleavage and polyadenylation,” the authors concluded.