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 are motifs found in DNA and RNA that can fold into tertiary structures. Until now, they have been studied experimentally mainly in humans and a few other species. Recently, predictions have been made with bacterial and archaeal genomes. Nevertheless, a global comparison of predicted G4s (pG4s) across and within the three living kingdoms has not been addressed. In this study, we aimed to predict G4s in genes and transcripts of all kingdoms of living organisms and investigated the differences in their distributions. The relation of the predictions with GC content was studied. It appears that GC content is not the only parameter impacting G4 predictions and abundance. The distribution of pG4 densities varies depending on the class of transcripts and the group of species. Indeed, we have observed that, in coding transcripts, there are more predicted G4s than expected for eukaryotes but not for archaea and bacteria, while in noncoding transcripts, there are as many or fewer predicted G4s in all species groups. We even noticed that some species with the same GC content presented different pG4 profiles. For instance, Leishmania major and Chlamydomonas reinhardtii both have 60% of GC content, but the former has a pG4 density of 0.07 and the latter 1.16.
G-quadruplexes (G4) are 3D structures that are found in both DNA and RNA. Interest in this structure has grown over the past few years due to both its implication in diverse biological mechanisms and its potential use as a therapeutic target, to name two examples. G4s in humans have been widely studied; however, the level of their study in other species remains relatively minimal. That said, progress in this field has resulted in the prediction of G4s structures in various species, ranging from bacteria to eukaryotes. These predictions were analysed in a previous study which revealed that G4s are present in all living kingdoms. To date, eleven different databases have grouped the various G4s depending on either their structures, on the proteins that might bind them, or on their location in the various genomes. However, none of these databases contains information on their location in the transcriptome of many of the implicated species. The GAIA database was designed so as to make this data available online in a user-friendly manner. Through its web interface, users can query GAIA to filter G4s, which, we hope, will help the research in this field. GAIA is available at: https://gaia.cobius.usherbrooke.ca
Amongst the wide array of alternative splicing events (ASE), the intrinsic mechanisms of intron retention have remained elusive. This particular type of ASE has long been characterized as an artifact, but recent studies have shown its implication in numerous diseases. It has also been revealed that numerous viruses choose to disrupt alternative splicing to escape cellular immune response and further their proliferation. The main focus of this study was to investigate the G-quadruplex role in Alternative Splicing Events (ASEs) that occur following Flavivirus infections. After having demonstrated that G-quadruplexes structures are mainly formed in Intron Retained Transcripts by RNA-seq, our attention turned toward the ULK3 gene, coding for a serine/threonine kinase regulating autophagy, an essential mechanism in the cellular response to stress and even pathogen infections. In this study, we revealed the presence of a G-quadruplex in the first intron of the ULK3 gene near the 3' splice site. Furthermore, we assayed the formation and stability of this G-quadruplex in vitro and showed that its formation affects IR, as demonstrated by comparisons between wild-type and mutant transfected mini-genes. Finally, we identified the specific RNA-binding protein signature for this G-quadruplex, thereby uncovering the novel role of G-quadruplexes in Alternative Splicing.
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