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Unveiling the biological effects of DNA G-quadruplex ligands through multi-omics data integration

ABSTRACT: G-quadruplexes (G4s) are non-canonical DNA structures that have proved to play a pivotal role in various biological processes, including telomere maintenance and gene expression regulation. Owing to their prevalence in tumor cells, G4s have emerged as promising targets for cancer therapy, with a substantial body of research demonstrating the potential of G4 ligands as anti-cancer tools. However, a more comprehensive understanding of G4 binders’ mode of action is imperative to successfully translate them into therapeutic agents. Herein, we employed a multi-omics approach, integrating transcriptomics, proteomics and metabolomics, to identify key signaling pathways that mediate the anti-cancer effects of well-characterized G4-binding agents (berberine, PDS and RHPS4) on HeLa cancer cells. Our results revealed that, under the investigated experimental conditions, berberine treatment only had negligible cellular effects, whereas PDS-treated HeLa cells underwent significant changes at the transcriptomic, proteomic and metabolomic levels, with marked impairment in glycolysis, antioxidant capacity, lipids and nucleotides biosynthetic processes. Notably, RHPS4 could selectively affect mitochondrial activity, possibly through the specific stabilization of mitochondrial G-quadruplex structures. Overall, our findings provide a valuable multi-omics perspective on the cellular changes driven by G-quadruplex binders, that may accelerate the development of G4-targeted therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286401 | GEO | 2025/05/20

REPOSITORIES: GEO

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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.

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Unveiling the biological effects of DNA G-quadruplex ligands through multi-omics data integration

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