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G-quadruplex structures regulate long-range transcriptional reprogramming to promote drug resistance in ovarian cancer [RNA-seq]

ABSTRACT: G-quadruplexes are secondary DNA structures which have been shown to have an impact on gene transcription via a variety of mechanisms, In this study we generate RNA-seq data of wildtype chemotherpay sensitive (PEO1 A) and chemostherapy resistant (PEO4 A) ovarian cancer cells to intersect with G-quadruplex mapping data to assess how transcription is impacted by G-quadruplex formation. In another variation of the PEO1/4 cell line, in which the PEO1 B cell line has a reversion mutation to reinstate BRCA2, we used the G-quadruplex stabilising molecule pyridostatin (PDS) to treat PEO1 B and its counterpart PEO4 B for either 0, 2 or 6 hours to see how stabilising G-quadruplexes effects gene expression in a temporal manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279501 | GEO | 2025/06/06

REPOSITORIES: GEO

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G-quadruplex structures regulate long-range transcriptional reprogramming to promote drug resistance in ovarian cancer [CUT&Tag]

Project description:Enhancers are regulatory elements of the genome involved in transcriptional regulation and reprogramming. Similarly, we propose that secondary DNA structures termed G-quadruplexes could also be impacting transcription in an enhancer based way via long-range interactions to bring together regulatory elements of the genome. In this study, we map G-quadruplex structures and h3k27ac enhancer marks in a paired ovarian cancer cell line; PEO1 and PEO4. We endeavour to use these findings to help link the transcriptional function of G-quadruplexes with enchancer in chemotherapy sensitive (PEO1) and chemotherapy resistant (PEO4) ovarian cancer cells.

2025-06-06 | GSE279641 | GEO

G-quadruplex structures regulate long-range transcriptional reprogramming to promote drug resistance in ovarian cancer [ChIP-seq]

Project description:G-quadruplex ChIP-seq has been performed to establish genomic maps of G-quadruplex structures in chemotherapy sensitive (PEO1) and chemotherapy resistant (PEO4) ovarian cancer cell lines to uncover how the changes in G-quadruplex landscape may contribute to the development of chemotherapy resistance for the first time.

2025-06-06 | GSE279497 | GEO

G-quadruplex structures regulate long-range transcriptional reprogramming to promote drug resistance in ovarian cancer [ATAC-seq]

Project description:Chromatin accessibilty is a key regulator of gene expression. In this study we aim to map accessible chromatin regions in both chemotherapy sensitive (PEO1) and chemotherapy resistant (PEO4) ovarian cancer cell lines, to intersect with RNA-seq data to see how chromatin architecture changes and impacts gene expression between the two cell lines.

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Innate immune response to G-quadruplex binders in cancer cells

Project description:G-quadruplex (G4) is non-canonical nucleic acid structure involved in a plethora of fundamental biological processes. In past decades, it has been studied as a promising pharmaceutical target for anticancer therapy. However, no G4-targeting agent has shown significant clinical effects up to date. Pyridostatin (PDS), a well-known G4 binder, can induce double-stranded DNA breaks and genome instability. We have recently shown that Pyridostatin (Pyridostatin) and other G4 binders can trigger micronuclei formation in cancer cells at non-cytotoxic concentrations. As micronuclei can play a crucial role in linking genome instability to innate immunity, we have here wondered whether G4 binders can induce immune gene activation in human MCF-7 breast cancer cells.

2021-07-14 | GSE161418 | GEO

G-Quadruplex structures are stable and detectable in human genomic DNA.

Project description:The G-quadruplex is an alternative DNA structural motif that is considered to be functionally important in the mammalian genome. Herein, we address the hypothesis that G-quadruplex structures can exist within double-stranded genomic DNA using a G-quadruplex-specific probe. An engineered antibody is employed to enrich for DNA containing G-quadruplex structures, followed by deep sequencing to detect and map G-quadruplexes at high resolution in genomic DNA from human breast adenocarcinoma cells. Our high sensitivity structure-based pull-down strategy enables the isolation of genomic DNA fragments bearing a single as well as multiple G-quadruplex structures. Stable G-quadruplex structures are found in sub-telomeres, gene bodies and gene regulatory regions. For a sample of identified target genes, we show that G-quadruplex stabilizing ligands can modulate transcription. These results confirm the existence of G-quadruplex structures and their persistence in human genomic DNA. Four independent libraries have been enriched in DNA G-quadruplex structures using a G-quadruplex-specific probe. One genomic input library was sequenced as control. Deep-sequencing of these libraries allowed the mapping of G-quadruplexes on the genome.

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G-quadruplex roles in transcription deciphered by comparative transcriptomic analyses

Project description:G-quadruplexes (G4) are non-canonical nucleic acid structures that can form at certain DNA or RNA guanine-rich sequences. G4 motifs are dispersed throughout the genome and considerably enriched at promoters, where they flank the transcription start site (TSS) and cluster at the 5’ end of the first intron, which suggests potential regulatory roles of quadruplexes in transcription. To improve our understanding of these roles, we have associated gene expression with the frequency of canonical G4 motifs near gene promoters and characterized perturbations caused by treatment with three G-quadruplex ligands, Pyridostatin and the two bisquinolinium compounds PhenDC3 and PhenDC6. We show that enrichment of G4 motifs characterizes the most actively transcribed genes, challenging the notion that quadruplexes chiefly exert negative regulation by blocking progress of RNA polymerase. G4 ligand-treatment altered splicing of transcripts at genes enriched for G4 motifs at the 5’-end of intron 1, suggesting that G-quadruplexes in the pre-mRNA can regulate splicing. Furthermore, our analysis also revealed some of the effects of G4 ligand treatment that likely reflect quadruplex-dependent replication stress leading to the induction of transcriptional signatures compatible with impaired cell cycle progression. Collectively, our results support the view that G-quadruplexes typically function as positive regulators of transcription, suggesting that quadruplexes may stabilize promoter architecture to enable efficient transcription. This analysis provides strong support for function of quadruplexes near the promoter as regulators of transcription and splicing.

2020-11-02 | GSE133419 | GEO

Differential proteomics of HeLa cells treated with PDS for 24 hours and untreated HeLa cells

Project description:Pyridostatin (PDS) is a well-known G-quadruplex (G4) inducer and stabilizer, yet its target genes have remained unclear. Herein, combining mass spectrometry based proteomics strategy with bioinformatics analysis, we revealed that PDS significantly downregulated 22 proteins, of which the genes contain rich G4 potential sequences, in HeLa cancer cells, consequently upregulating 16 proteins remarkably. The PDS-regulated proteins appeared to work synergistically to activate cyclin and cell cycle regulation, and to restrain the inhibition of ARE-mediated mRNA decay pathway, suggesting that PDS itself is not a potential anticancer agent, at least towards HeLa cancer.

2022-05-19 | PXD029521 | Pride

YY1 Interacts with G quadruplex DNA to Regulate Gene Expression

Project description:We systematically analyzed the alterations in mRNA transcriptome evoked by knockdown of YY1 with or without pyridostatin (PDS) treatment. Statistical analysis showed a strong correlation between PDS-regulated and YY1-regulated genes (Pearson r > 0.67), underscoring the role of YY1-G4 structure interaction in YY1-mediated gene regulation. Moreover, the RNA-Seq results revealed that YY1 can positively or negatively regulate the expression of genes through its interaction with G4 structures.

2020-08-27 | GSE142075 | GEO

Homo sapiens

Project description:PEO1/PEO4 Exome Sequence

| PRJNA299834 | ENA

DNA G-quadruplex structure participates in regulation of lipid metabolism through Acyl-CoA binding protein

Project description:G-quadruplex structure (G4) is a type of DNA secondary structure that widely exists in the genomes of many organisms. G4s are believed to participate in multiple biological processes. Acyl- CoA binding protein (ACBP), a ubiquitously expressed and highly conserved protein in eukaryotic cells, plays important roles in lipid metabolism by transporting and protecting acyl-CoA esters. Here, we report the functional identification of a G4 in the promoter of the ACBP gene in silkworm and human cancer cells. We found that G4 exists as a conserved element in the promoters of ACBP genes in invertebrates and vertebrates. The BmACBP G4 bound with G4-binding protein LARK regulated BmACBP transcription, which was blocked by the G4 stabilizer pyridostatin (PDS) and G4 antisense oligonucleotides. PDS treatment with 5 th instar silkworm larvae decreased the BmACBP expression and triacylglycerides (TAG) level, resulting in reductions in fat body mass, body size and weight and growth and metamorphic rates. PDS treatment and knocking out of the HsACBP G4 in human hepatic adenocarcinoma HepG2 cells inhibited the expression of HsACBP and decreased the TAG level and cell proliferation. Altogether, our findings suggest that G4 of the ACBP genes is involved in regulation of lipid metabolism processes in invertebrates and vertebrates.

2022-05-04 | GSE201939 | GEO

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