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.

Keywords: DNA bases modifications; G-quadruplex; G-quartet; chromatin architecture; epigenetics; histone post-translational modifications; histone-modifying activities; noncoding RNA; nucleosome remodeling; post-transcriptional regulation.

Figure 1

Chemical structures of G-quartet and G-quadruplex. (A) Structural arrangement of the G-quartet, highlighting the hydrogen bonding network between the Hoogsteen and Watson–Crick faces of the coplanar guanine bases. The attached deoxyribose sugars are shown together with a centrally placed metal ion. (B) The conventional consensus sequence for a G-quadruplex. (C) Side view of the schematic diagram showing an intramolecular antiparallel G-quadruplex formed by the stacking of three G-quartets. Strand polarity and anticlockwise rotation are indicated.

Figure 2

Chemical structure of canonical and biochemically modified nitrogenous bases discussed in this review.

Figure 3

Interplay between G4 structures and the epigenetic machinery. (A) Schematic drawing indicating loss of histone epigenetic memory following DNA replication at sites with G4 structures in cells lacking either REV1 or FANCJ. (B) Mechanistic model showing that G4 structures can act as docking sites for several classes of epigenetic players. (C) Schematic model of enhancer–promoter interaction mediated by an intermolecular G4 structure formed by two distinct half G4s (indicated by asterisks).

Figure 4

Molecular processes modulated by G4 structures formed in coding and noncoding RNA transcripts. A schematic drawing indicating the parallel topology adopted by RNA G4s is shown.