The Role of BAZ2-dependent Chromatin Remodeling in Suppressing G4 DNA Structures and Associated Genomic Instability [INDUCE-seq]
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ABSTRACT:
PROVIDER: PRJNA1234547 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32652362.fastq.gz | Fastqsanger.gz | |||
| SRR32652363.fastq.gz | Fastqsanger.gz | |||
| SRR32652364.fastq.gz | Fastqsanger.gz | |||
| SRR32652365.fastq.gz | Fastqsanger.gz | |||
| SRR32652366.fastq.gz | Fastqsanger.gz |
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Project description:DNA G-quadruplexes (G4s) are secondary structures with significant roles in regulating genome function and stability. Dysregulation of the dynamic formation of G4s is linked to genomic instability and disease, but the underlying mechanisms are not fully understood. In this study, we conducted a screen of chromatin-modifying enzymes and identified nine potential inhibitors of G4 formation, including seven that were not previously characterized. Among these, we highlight the role of BAZ2 chromatin remodelers as key suppressors of G4 DNA and G4-related genome instability. Depletion of BAZ2 subunits led to increased G4 formation, especially at transcriptional regulatory elements. BAZ2B was found to associate with G4 loci, suggesting that it plays a direct role in suppressing G4s. While BAZ2-deficient cells exhibited modest genomic instability, treatment with the G4-stabilizing ligand BRACO19 exacerbated double-strand breaks (DSBs), highlighting its utility as a tool to study G4-dependent genome instability. DSB profiling using INDUCE-seq uncovered distinct breakage patterns around G4s, further underscoring the impact of G4s on genome integrity. Notably, we found that within G4s, G repeats were more susceptible to DSBs than loops. These results establish BAZ2 chromatin remodeling complexes as direct regulators of G4 dynamics and provide new insights into G4-dependent genome instability.
2025-03-11 | GSE291629 | GEO
Project description:DNA G-quadruplexes (G4s) are secondary structures with significant roles in regulating genome function and stability. Dysregulation of the dynamic formation of G4s is linked to genomic instability and disease, but the underlying mechanisms are not fully understood. In this study, we conducted a screen of chromatin-modifying enzymes and identified nine potential inhibitors of G4 formation, including seven that were not previously characterized. Among these, we highlight the role of BAZ2 chromatin remodelers as key suppressors of G4 DNA and G4-related genome instability. Depletion of BAZ2 subunits led to increased G4 formation, especially at transcriptional regulatory elements. BAZ2B was found to associate with G4 loci, suggesting that it plays a direct role in suppressing G4s. While BAZ2-deficient cells exhibited modest genomic instability, treatment with the G4-stabilizing ligand BRACO19 exacerbated double-strand breaks (DSBs), highlighting its utility as a tool to study G4-dependent genome instability. DSB profiling using INDUCE-seq uncovered distinct breakage patterns around G4s, further underscoring the impact of G4s on genome integrity. Notably, we found that within G4s, G repeats were more susceptible to DSBs than loops. These results establish BAZ2 chromatin remodeling complexes as direct regulators of G4 dynamics and provide new insights into G4-dependent genome instability.
2025-01-05 | GSE285882 | GEO
Project description:DNA G-quadruplexes (G4s) are secondary structures with significant roles in regulating genome function and stability. Dysregulation of the dynamic formation of G4s is linked to genomic instability and disease, but the underlying mechanisms are not fully understood. In this study, we conducted a screen of chromatin-modifying enzymes and identified nine potential inhibitors of G4 formation, including seven that were not previously characterized. Among these, we highlight the role of BAZ2 chromatin remodelers as key suppressors of G4 DNA and G4-related genome instability. Depletion of BAZ2 subunits led to increased G4 formation, especially at transcriptional regulatory elements. BAZ2B was found to associate with G4 loci, suggesting that it plays a direct role in suppressing G4s. While BAZ2-deficient cells exhibited modest genomic instability, treatment with the G4-stabilizing ligand BRACO19 exacerbated double-strand breaks (DSBs), highlighting its utility as a tool to study G4-dependent genome instability. DSB profiling using INDUCE-seq uncovered distinct breakage patterns around G4s, further underscoring the impact of G4s on genome integrity. Notably, we found that within G4s, G repeats were more susceptible to DSBs than loops. These results establish BAZ2 chromatin remodeling complexes as direct regulators of G4 dynamics and provide new insights into G4-dependent genome instability.
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Project description:The Role of BAZ2-dependent Chromatin Remodeling in Suppressing G4 DNA Structures and Associated Genomic Instability [G4]
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Project description:The Role of BAZ2-dependent Chromatin Remodeling in Suppressing G4 DNA [HA] Structures and Associated Genomic Instability
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Project description:G4 are noncanonical secondary structures consist in stacked tetrads of Hoogsteen hydrogen-bonded guanines bases. An essential feature of G-quadruplexes is their intrinsic polymorphic nature. Indeed, depending on the length and the composition of the sequence, as well as the environmental conditions (including the nature and concentration of metal cations, and local molecular crowding), a G-quadruplex-forming sequence can adopt different topologies in which the strands are in parallel or antiparallel conformations, with the co-existence of different types of loops (lateral, diagonal or propeller) with variable lengths. The impact of G4 on cellular metabolism is associated with protein or enzymatic factors that promote, inhibits or resolve these structures. Thus, the major impact of G4 on the human cell metabolism is associated with genetic defects affecting proteins that counteract their formation. Although a large number of proteins able to bind and/or "to resolve" G-quadruplex structures have been identified in vitro, less is known about their mode of interaction with G-quadruplex, their specificity versus the topology and finally their specificity for G4 structures relatively to G-rich single-stranded sequences. In this study we aimed to identify and characterize human proteins interacting with locked G4 structures.
2021-07-16 | PXD021003 | Pride
Project description: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.
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Project description:G-quadruplexes (G4s) and R-loops are non-canonical DNA structures that can play regulatory functions of basic nuclear processes and can trigger DNA damage and genome instability. We here show that specific G4 ligands can stabilize G4s and simultaneously increase R-loop levels in human cancer cells likely by spreading DNA:RNA heteroduplexes to adjacent regions containing G4 structures. DNA cleavage and DNA damage response induced by G4 ligands were rescued by overexpression of exogenous RNaseH1 in cancer cells independently of BRCA2 status. The data thus show that R-loops are involved in the induction of DNA damage by chemical G4 stabilization. In addition, G4 ligands trigger the formation of micronuclei, particularly in BRCA2-silenced cancer cells, in an R-loop dependent manner. Our results uncover the mechanism of genome instability caused by G4 ligands and can open to the development of unexpected anticancer strategies using G4-targeted agents.
2018-12-27 | GSE115957 | GEO
Project description:G-rich DNA sequences can form four-stranded G-quadruplex (G4) secondary structures and are linked to fundamental biological processes such as transcription, replication and telomere maintenance. G4s are also implicated in promoting genome instability, cancer and other diseases. Here, we describe a detailed G4 ChIP-seq method that robustly enables the determination of G4 structure formation genome-wide in chromatin. This protocol adapts traditional ChIP-seq for the detection of DNA secondary structures through the use of a G4-structure-specific phage display antibody with refinements in chromatin immunoprecipitation followed by high-throughput sequencing. Beginning with chromatin isolation and antibody preparation the entire protocol can be completed in less than 1 week including computational analysis.
2017-11-15 | GSE99205 | GEO
Project description:Nucleic acids can fold into G-quadruplex (G4) structures that can fine tune biological processes. Proteins are required to recognize G4 structures and coordinate their function. We identify Zuo1 as a novel G4-binding protein in a yeast one-hybrid screen. Biochemical and molecular experiments in yeast confirm that Zuo1 specifically binds to G4 structures in vitro and in vivo. In vivo in the absence of Zuo1 less G4 structures form, cell growth slows and cells become UV sensitive. Subsequent experiments reveal that these cellular changes are due to reduced levels of G4 structures. Interestingly, Zuo1 function and binding to G4 structures results in the recruitment of nucleotide excision repair (NER) factors, which has a positive effect on genome stability. Cells lacking functional NER as well as Zuo1 accumulate G4s structures, which become accessible for translesion synthesis. Our results suggest a model in which Zuo1 supports NER function and regulates the choice of the DNA repair pathway near G4 structures.
2020-06-23 | GSE149502 | GEO