G-quadruplex structures mark human regulatory chromatin

Abstract

G-quadruplex (G4) structural motifs have been linked to transcription, replication and genome instability and are implicated in cancer and other diseases. However, it is crucial to demonstrate the bona fide formation of G4 structures within an endogenous chromatin context. Herein we address this through the development of G4 ChIP-seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We find ∼10,000 G4 structures in human chromatin, predominantly in regulatory, nucleosome-depleted regions. G4 structures are enriched in the promoters and 5' UTRs of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as MYC. Strikingly, de novo and enhanced G4 formation are associated with increased transcriptional activity, as shown by HDAC inhibitor-induced chromatin relaxation and observed in immortalized as compared to normal cellular states. Our findings show that regulatory, nucleosome-depleted chromatin and elevated transcription shape the endogenous human G4 DNA landscape.

Oxidative DNA damage is epigenetic by regulating gene transcription via base excision repair

“…These control experiments do not rule out all sequence context effects or the role of all protein activators and repressors but they do provide strong support for this sequence to adopt a G-quadruplex fold to induce the gene. The observation of transcriptional activation by G4 formation in the present study is consistent with a recent demonstration that these folds in promoters up-regulate transcription on the basis of G-quadruplex ChIP-Seq in tandem with RNA-Seq analysis (9).…”

“…One gene in particular is vascular endothelial growth factor (VEGF), for which OG was found in the G-rich potential G-quadruplex sequence (PQS) (7) demonstrated to be responsible for transcriptional regulation of the gene (8). Strong cellular evidence for enhancement of transcription via folding of promoter G-quadruplexes was recently demonstrated by the Balasubramanian laboratory (9). Therefore, we hypothesize formation of OG in the VEGF PQS under oxidative stress conditions functions as a signaling mark to unmask the G-quadruplex fold, thus leading to transcriptional activation.…”

On the binding modes of metal NHC complexes with DNA secondary structures: implications for therapy and imaging

“…83 It was revealed that these G4 sequences were especially present in non-nucleosomal regions in the genome and that they would enrich in promoter regions of genes. Promoter G4s occur once per promoter region and although small in size, they…”

G-quadruplex–forming promoter sequences enable transcriptional activation in response to oxidative stress

“…Non-Watson-Crick secondary structures of nucleic acids, and in particular, G4 structures in DNA is an area of extremely active research (12)(13)(14)(15)(16). Although G4 structures were initially described in the context of telomeres, recent genomic data revealed tens of thousands of sequences throughout the genome (14,17) that, in principle, could form G4 structures, called potential G-quadruplex-forming sequences (PQS).…”

“…Although G4 structures were initially described in the context of telomeres, recent genomic data revealed tens of thousands of sequences throughout the genome (14,17) that, in principle, could form G4 structures, called potential G-quadruplex-forming sequences (PQS). Many of these sequences, when folded as G4s, can bind with high-affinity cellular proteins or transcription factors (16), but the relevance and physiological role of such interactions are still actively investigated.…”