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Relevance of G-quadruplex structures to pharmacogenetics.

ABSTRACT: G-quadruplexes are non-canonical secondary structures formed within nucleic acids that are involved in modulating cellular processes such as replication, gene regulation, recombination and epigenetics. Within genes, there is mounting evidence of G-quadruplex involvement in transcriptional and post transcriptional regulation. We report the presence of potential G-quadruplex motifs within relevant sites of some important pharmacogenes and discuss the possible implications of this on the function and expression of these genes. Appreciating the location and potential functions of these motifs may be of value when considering the impacts of some pharmacogenetic variants. G-quadruplexes are also the focus of drug development efforts in oncology and we highlight the broader pharmacological implications of treatment strategies that may target G-quadruplexes.

SUBMITTER: Cree SL

PROVIDER: S-EPMC4085647 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Relevance of G-quadruplex structures to pharmacogenetics.

Cree Simone L SL Kennedy Martin A MA

Frontiers in pharmacology 20140708

G-quadruplexes are non-canonical secondary structures formed within nucleic acids that are involved in modulating cellular processes such as replication, gene regulation, recombination and epigenetics. Within genes, there is mounting evidence of G-quadruplex involvement in transcriptional and post transcriptional regulation. We report the presence of potential G-quadruplex motifs within relevant sites of some important pharmacogenes and discuss the possible implications of this on the function a ...[more]

PMID: 25071578

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Project description:DNA secondary structures are important for fundamental genome functions such as transcription and replication1. The G-quadruplex (G4) structural motif has been linked to gene regulation2,3 and genome instability4,5 and may be important to cancer development and other diseases6-8. Recently, ~700,000 discrete G4s have been observed in naked human single-stranded genomic DNA using G4-seq, a high-throughput sequencing technique that detects structural features in vitro.9 It is of vital importance to investigate G4 structures within an endogenous chromatin context, which until now remained elusive10,11. Herein, we address this via the development of G4 ChIP-seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We identified ~10,000 endogenous G4 structures and show that G4s are predominantly seen in regulatory, nucleosome-depleted, chromatin regions. G4s were enriched in the promoters and 5âUTR regions of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as MYC. Reorganization of the chromatin landscape using a histone deacetylase inhibitor, resulted in de novo G4 formation in new and more prominent regulatory, nucleosome-depleted regions associated with increased transcriptional output. Our findings suggest a striking relationship between promoter nucleosome-depleted regions, G4 formation and elevated transcriptional activity. Comparison between normal human epidermal keratinocytes and their immortalized counterparts revealed a ï¾7-fold greater G4 abundance in immortalized cells, of which 80 % were found in regulatory, nucleosome-depleted regions common to both cell types. Consequently, cells exhibiting more G4s displayed significantly increased transcriptional output and were more sensitive to growth inhibition by a small molecule G4 ligand. Overall, our results provide new mechanistic insights into where and when DNA adopts G4 structure in vivo. Our findings show for the first time that regulatory, nucleosome-depleted chromatin and transcriptional states predominantly shape the endogenous G4 DNA landscape. Two cell lines, treated with entinostat or untreated, analyzed to detect gene expression differences, presence of G-Qudruplexes and chromatin state. Each combination of conditions replicated in duplicates or triplicates.

Dataset Information

Relevance of G-quadruplex structures to pharmacogenetics.

Publications

Relevance of G-quadruplex structures to pharmacogenetics.

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