Biological relevance and therapeutic potential of G-quadruplex structures in the human noncoding transcriptome

Abstract

Noncoding RNAs are functional transcripts that are not translated into proteins. They represent the largest portion of the human transcriptome and have been shown to regulate gene expression networks in both physiological and pathological cell conditions. Research in this field has made remarkable progress in the comprehension of how aberrations in noncoding RNA drive relevant disease-associated phenotypes; however, the biological role and mechanism of action of several noncoding RNAs still need full understanding. Besides fulfilling its function through sequence-based mechanisms, RNA can form complex secondary and tertiary structures which allow non-canonical interactions with proteins and/or other nucleic acids. In this context, the presence of G-quadruplexes in microRNAs and long noncoding RNAs is increasingly being reported. This evidence suggests a role for RNA G-quadruplexes in controlling microRNA biogenesis and mediating noncoding RNA interaction with biological partners, thus ultimately regulating gene expression. Here, we review the state of the art of G-quadruplexes in the noncoding transcriptome, with their structural and functional characterization. In light of the existence and further possible development of G-quadruplex binders that modulate G-quadruplex conformation and protein interactions, we also discuss the therapeutic potential of G-quadruplexes as targets to interfere with disease-associated noncoding RNAs.

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

“…Despite a growing number of RNA G4s being identified and characterized, reports on their interaction with G4 ligands are less common. Nevertheless, other RNA secondary structures have been extensively studied for therapeutic and diagnostic purposes [ 37 ]. Since RNA G4s are non-randomly distributed in transcriptome and present in several important genes and regulatory regions, designing G4 ligands that stabilize or destabilize such structures is seen as an attractive therapeutic and diagnostic strategy for various diseases such as cancer and neurological disorders [ 37 ].…”

“…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 ]. Those sequences are mainly located in both 5′ and 3′UTR, as well as at the splicing junction of mRNA and noncoding RNAs, being of utmost importance in regulatory post-transcriptional mechanisms [ 37 ].…”

“…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 ]. Those sequences are mainly located in both 5′ and 3′UTR, as well as at the splicing junction of mRNA and noncoding RNAs, being of utmost importance in regulatory post-transcriptional mechanisms [ 37 ]. In the last few years, several reports have highlighted the importance of G4s in the transcriptome by employing G4 sequencing high-throughput approaches [ 38 , 39 , 40 , 41 ].…”

Identification and targeting of G-quadruplex structures inMALAT1long non-coding RNA

“…However, few works have elucidated RNA structural elements in lncRNAs (78)(79)(80)(81). rG4s, being non-classical RNA structural motifs, have been studied more extensively in mRNAs, but less so in ncRNAs such as lncRNAs (13,14,82). Besides the wellcharacterized rG4s in human telomerase RNA (hTR) (30,51,83) and Telomeric repeatcontaining RNA (TERRA) (31,32,84), there is so far only a handful of rG4 reported in lncRNAs, including FLJ39051(GSEC) (29), LUCAT1 (49), and NEAT1 (33).…”

“…The advent of next-generation sequencing has enabled the robust identification of non-coding RNAs (ncRNAs), which significantly facilitated our understanding and investigation of their structures and functions in cells. Interestingly, latest studies have begun to explore the existence and roles of rG4s in ncRNAs (13,14) such as long non-coding RNAs (lncRNAs) (29)(30)(31)(32)(33), miRNAs (34)(35)(36), Piwi-interacting RNAs (piRNAs) (37,38), ribosomal RNAs (rRNAs) (39,40), transfer RNAs (tRNAs) (41,42), and the initial findings were exciting. They revealed ncRNA rG4s to have key regulatory roles in gene expression, RNA metabolism, and protein recognition and function (13,14,43).…”