Epigenetic Modulation of Chromatin States and Gene Expression by G-Quadruplex Structures

Abstract

G-quadruplexes are four-stranded helical nucleic acid structures formed by guanine-rich sequences. A considerable number of studies have revealed that these noncanonical structural motifs are widespread throughout the genome and transcriptome of numerous organisms, including humans. In particular, G-quadruplexes occupy strategic locations in genomic DNA and both coding and noncoding RNA molecules, being involved in many essential cellular and organismal functions. In this review, we first outline the fundamental structural features of G-quadruplexes and then focus on the concept that these DNA and RNA structures convey a distinctive layer of epigenetic information that is critical for the complex regulation, either positive or negative, of biological activities in different contexts. In this framework, we summarize and discuss the proposed mechanisms underlying the functions of G-quadruplexes and their interacting factors. Furthermore, we give special emphasis to the interplay between G-quadruplex formation/disruption and other epigenetic marks, including biochemical modifications of DNA bases and histones, nucleosome positioning, and three-dimensional organization of chromatin. Finally, epigenetic roles of RNA G-quadruplexes in post-transcriptional regulation of gene expression are also discussed. Undoubtedly, the issues addressed in this review take on particular importance in the field of comparative epigenetics, as well as in translational research.

DNA G-Quadruplexes Contribute to CTCF Recruitment

“…Our findings support G4 involvement in chromatin organization and partially explain G4 enrichment at TAD boundaries [6]. These findings also add to the growing body of links between G4s and the epigenetic machinery, highlighting the prospects of G4s as epigenetic drug targets and raising new concerns about possible side effects of G4stabilizing small molecule therapeutics [2,42]. Moreover, evidence for G4-CTCF binding adds complexity to the current vision of enhancer-promoter interactions at G4-prone sites [6,43].…”

“…Thus, persistent G4s appear to be more challenging than transient ones in terms of fine-tuning with exogenous compounds. We hope that our results along with other emerging evidence for G4 interference with 3D genome organization [42] will stimulate studies of G4-targeting agents as epigenetic drug candidates.…”

A G-Quadruplex-Binding Small Molecule and the HDAC Inhibitor SAHA (Vorinostat) Act Synergistically in Gemcitabine-Sensitive and Resistant Pancreatic Cancer Cells

“…Thus, the action of SAHA would be to facilitate the formation of a greater number of quadruplex sites for a given CM03 concentration that would be available with CM03 alone, resulting in growth arrest at lower drug concentrations that with either drug alone. In addition, the induction of quadruplex formation by CM03 would be expected to facilitate chromatin relaxation [ 24 , 25 , 26 , 27 ], so augmenting the action of SAHA.…”

“…The existence of G4s has been demonstrated in live cancer cells [ 22 ] and G4-enriched genes have been found to occur in patient-derived breast cancer xenografts [ 23 ]. Interestingly, G4s are also directly implicated in epigenetic remodeling via histone modification and DNA methylation regulation during DNA replication [ 16 , 17 , 24 , 25 , 26 ]. This potentially involves the high affinity binding of G4s to epigenetic factors such as DNA methyltransferases (DNMTs) [ 27 ].…”

Metal-Based G-Quadruplex Binders for Cancer Theranostics

“…The G-quartet is stabilized by monovalent cations such as potassium (K + ) and sodium (Na + ) and to a lesser extent lithium (Li + ), which coordinate with the central electronegative carbonyl O6 atoms of the G-quartet core [ 5 ]. G4 structures formed in the presence of K + are considered to be biologically more relevant due to its higher intracellular concentration (≈140 mM) and its quasi -perfect fitting in the cavity formed between adjacent G-quartets [ 6 ]. G4s display a wide variety of topologies, depending on the sequence, loop size, strand stoichiometry (intramolecular or intermolecular), strand polarity and orientation (parallel or antiparallel), and the cation present in solution [ 7 ].…”