DNA G‐Quadruplexes (G4s) Modulate Epigenetic (Re)Programming and Chromatin Remodeling

Abstract

Here, the emerging data on DNA G‐quadruplexes (G4s) as epigenetic modulators are reviewed and integrated. This concept has appeared and evolved substantially in recent years. First, persistent G4s (e.g., those stabilized by exogenous ligands) were linked to the loss of the histone code. More recently, transient G4s (i.e., those formed upon replication or transcription and unfolded rapidly by helicases) were implicated in CpG island methylation maintenance and de novo CpG methylation control. The most recent data indicate that there are direct interactions between G4s and chromatin remodeling factors. Finally, multiple findings support the indirect participation of G4s in chromatin reshaping via interactions with remodeling‐related transcription factors (TFs) or damage responders. Here, the links between the above processes are analyzed; also, how further elucidation of these processes may stimulate the progress of epigenetic therapy is discussed, and the remaining open questions are highlighted.

Promoter G-quadruplexes and transcription factors cooperate to shape the cell type-specific transcriptome

“…As a further proof, AP-1 and SP1 were co-immunoprecipitated using anti-G4 primary antibody ( Figure 4D, lanes 2-3) and, vice versa, primary antibodies against SP1 and AP-1 co-immunoprecipitated the anti-G4 antibody added to the samples as marker of G4 regions ( Figure 4D, lanes 4-8), proof that these TFs interact with their binding sites in the presence of folded G4s (Figure 4D). These data indicate that TFs AP-1 and SP1 are strictly linked to G4s and suggest that G4s are exploited by cells to facilitate TF interaction with the DNA: this effect is reached by G4-mediated exposure of the binding region or altered DNA methylation state, as G4s were reported to prevent CpG island methylation, condition which is required for transcription initiation 3,14,27 . An alternative possibility is that TF binding to G4 regions stimulates G4 folding to maintain the underneath chromatin in a transcription permissive state.…”

“…Specific gene programs are activated in cells to maintain their diversity and identity. Chromatin organization and gene expression are modulated by a complex interplay between epigenetic marks (DNA methylation, histone modification, nucleosome positioning) and binding of core TFs to regulatory DNAs[1][2][3] . We hypothesized that G4s cooperated with TFs in the maintenance of cell-specific gene expression programs, contributing to the establishment of the transcriptome.…”

Higher Order Organization of the mtDNA: Beyond Mitochondrial Transcription Factor A

“…The occurrence of GQs within the DNA is not random, and is notably conserved across species, thus supporting selective constraints and hence potential functional importance (Murat and Balasubramanian, 2014). Moreover, whereas transient GQs correlate with binding sites of chromatin remodeling-related transcription factors, genome-wide sites with more stable GQs have been implicated in replication stalling and inhibition of chromatin remodeling (Varizhuk et al, 2019), which support their involvement in regulation of higher order DNA organization. For example, GQ-ChIP-seq experiments revealed that most GQs tend to form within nucleosome-depleted regions with increased transcription activity (Hansel-Hertsch et al, 2016).…”

“…For example, GQ-ChIP-seq experiments revealed that most GQs tend to form within nucleosome-depleted regions with increased transcription activity (Hansel-Hertsch et al, 2016). As GQ structures are mostly resolved by RecQ helicases (Mendoza et al, 2016;Sauer and Paeschke, 2017;Varizhuk et al, 2019), it is noteworthy that one such helicase, RecQ4, is transported into the mitochondria, interacts with DNA POLG and promotes mtDNA replication (Ding and Liu, 2015). Indeed, due to the asymmetric composition of nucleotides in the heavy (more guanine-rich) and light (more cytosine-rich) strands of mtDNA, the heavy mtDNA strand is prone to GQ formation.…”

Exploring the Interaction of Curaxin CBL0137 with G-Quadruplex DNA Oligomers

“…G-quadruplexes play a role in several key cellular processes, including gene transcription, chromatin epigenetics and DNA recombination. G-quadruplex DNA is found in key regulatory regions of the cell such as promoters of proto-oncogenes ( c-myc , bcl-2 and c-Kit ) [ 20 ]. Stabilization of the folded G-quadruplexes due to ligand interactions is proposed to inhibit the binding of transcription factors, leading to downstream silencing of oncogene expression [ 21 , 22 , 23 ].…”