Where are G-quadruplexes located in the human transcriptome?

Abstract

It has been demonstrated that RNA G-quadruplexes (G4) are structural motifs present in transcriptomes and play important regulatory roles in several post-transcriptional mechanisms. However, the full picture of RNA G4 locations and the extent of their implication remain elusive. Solely computational prediction analysis of the whole transcriptome may reveal all potential G4, since experimental identifications are always limited to specific conditions or specific cell lines. The present study reports the first in-depth computational prediction of potential G4 region across the complete human transcriptome. Although using a relatively stringent approach based on three prediction scores that accounts for the composition of G4 sequences, the composition of their neighboring sequences, and the various forms of G4, over 1.1 million of potential G4 (pG4) were predicted. The abundance of G4 was computationally confirmed in both 5′ and 3′UTR as well as splicing junction of mRNA, appreciate for the first time in the long ncRNA, while almost absent of most of the small ncRNA families. The present results constitute an important step toward a full understanding of the roles of G4 in post-transcriptional mechanisms.

G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions

“…Furthermore, the presence of the 2′-OH group in the ribose ring favors the parallel topology, making them more attractive as target molecules [ 34 ]. To date, using computational approaches, more than 1.1 million guanine-rich sequences h with the ability to fold into RNA G4 have been identified [ 35 ]. RNA G4s were shown to exist in human cells by using the specific G4 antibody BG4 [ 36 ] and, in the same way as DNA G4s, those sequences are non-randomly distributed in the transcriptome [ 37 ].…”

Ligands as Stabilizers of G-Quadruplexes in Non-Coding RNAs

“…In 2015, bioinformatics predictive tools, using a GQRS mapper [43], suggested the presence of at least one rG4 motif in 16% of human pre-miRNA stem−loop regions [44]. Recently, Perreault and coworkers, using a new approach, reported that only 2% of pre-miRNA contain a putative rG4 motif [22]. This analysis confirms a competition between G4, and the secondary structures recognized by Dicer identifying that rG4 overlapping the Dicer cleavage site in 9% of the miRNAs.…”

“…Biophysical studies highlighted several parameters influencing rG4 conformations, including the number of G-quartet stacks, the length/sequence composition of the loops, the occurrence of bulges, the availability/nature of the central ion, the sequence in flanking regions, and the ligands interaction/stabilization of the rG4s [12]. Moreover, computational algorithms and next-generation sequencing (NGS), as well as the use of fluorescent light-up probes, have highlighted the location and biological functions of rG4s in untranslated regions (UTR) of mRNA sequences [21], and more recently in ncRNAs [22]. This was key to driving subsequent functional analyses that revealed the biological relevance of rG4s in the post-transcriptional control of gene expression impacting cellular processes.…”

“…Moreover, computational algorithms and next-generation sequencing (NGS), as well as the use of fluorescent light-up probes, have highlighted the location and biological functions of rG4s in untranslated regions (UTR) of mRNA sequences [21], and more recently in ncRNAs [22]. This was key to driving subsequent functional analyses that revealed the biological relevance of rG4s in the post-transcriptional control of gene expression impacting cellular processes.…”

Guanine Nucleotide-Binding Protein-Like 1 (GNL1) binds RNA G-quadruplex structures in genes associated with Parkinson’s disease

“…In order to investigate the location of the pG4 within the mRNA, their positions were established for each of the isoform variants associated with the neurogenerative diseases: 21% were located in the 5ʹUTR, 46% in the CDS region and 33% in the 3ʹUTR. At first view, the abundance of pG4 located within the CDS region seems surprising, because G4s are globally known to be enriched in both the 5ʹ and 3ʹUTRs [33].…”