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Whole genome mapping of DNA G-quadruplexes in multiple species by G4-seq

ABSTRACT: The identification of DNA G-quadruplexes (G4s) in the genome is important to study different biological processes in which these structures play a role, such as genome rearrangement, transcriptional regulation and DNA replication. G4-seq allowed the high-throughput experimental mapping of G-quadruplexes in the human genome. We developed here an improved version of this method, named G4-seq2, which we applied to generate G-quadruplexes genomic maps for 12 species, selected as important models organism to study development or as pathogens of clinical relevance. Those multi-species maps, publicly available for the community, will allow to further understand the design principle of G-quadruplex formation in genomic context, to study G-quadruplex biology in those model organisms, to predict ligand targeting for therapeutic usage and to design G-quadruplex computational predictors based on genome-wide experimental measurements.

ORGANISM(S): Trypanosoma brucei Escherichia coli Arabidopsis thaliana Mus musculus Danio rerio Saccharomyces cerevisiae Homo sapiens Plasmodium falciparum Caenorhabditis elegans Leishmania major Cereibacter sphaeroides Drosophila melanogaster

PROVIDER: GSE110582 | GEO | 2018/08/01

REPOSITORIES: GEO

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Native G-quadruplexes Stabilization Impairs Transcription Initiation

Project description:G-quadruplexes (G4s) are noncanonical DNA secondary structures formed through the self-association of guanines. They are distributed genome-widely and participate in multiple biological processes including gene transcription, and quadruplex-targeted ligands serve as potential therapeutic agents for DNA-targeted therapies. However, the roles of G-quadruplexes in transcriptional regulation remains elusive. Here, we establish a sensitive G4-CUT&Tag method for genome-wide profiling of native G-quadruplexes with high resolution and specificity. We find that native G-quadruplex signals are cell-type specific and are associated with transcriptional regulatory elements with active epigenetic modifications. Promoter-proximal RNA polymerase II pausing promotes native G-quadruplex formation, oppositely, G-quadruplex stabilization by quadruplex-targeted ligands globally reduces RNA polymerase II occupancy at gene promoters as well as nascent RNA synthesis. Moreover, G-quadruplex stabilization modulates chromatin states and impedes transcription initiation via inhibiting the loading of general transcription factors to promoters.Together, these studies reveal a reciprocal regulation between native G-quadruplex dynamics and gene transcription in the genome, which will deepen our knowledge of G-quadruplex biology towards considering therapeutically targeting G-quadruplexes in human diseases.

2021-07-19 | GSE178668 | GEO

Parallel G-quadruplexes recruit the HSV-1 transcription factor ICP4 to promote viral transcription in herpes virus-infected human cells

Project description:G-quadruplexes (G4s) are four-stranded nucleic acid structures abundant at gene promoters. They can adopt several distinctive conformations. G4s have been shown to form in the herpes simplex virus-1 (HSV-1) genome during its viral cycle. Here by cross-linking/pull-down assay we identified ICP4, the major HSV-1 transcription factor, as the protein that most efficiently interacts with viral G4s during infection. ICP4 specific and direct binding and unfolding of parallel G4s, including those present in HSV-1 immediate early gene promoters, induced transcription in vitro and in infected cells. This mechanism was also exploited by ICP4 to promote its own transcription. Proximity ligation assay allowed visualization of G4-protein interaction at the single selected G4 in cells. G4 ligands inhibited ICP4 binding to G4s. Our results indicate the existence of a well-defined G4-viral protein network that regulates the productive HSV-1 cycle. They also point to G4s as elements that recruit transcription factors to activate transcription in cells.

2021-09-10 | PXD024743 | Pride

G4 quadruplex landscape and its regulation revealed by a new antibody capture method

Project description:Currently, the identification of G4 quadruplexes in vivo depends on a published and widely used G4-ChIP protocol (PMID: 29470465) that uses the anti-G4 antibody to captures the quadruplexes like regular chromatin. This method is challenged by some false positives and false negatives in G4-quadruplex capture. We have developed an antibody capture G4-ChIP (AbC G4-ChIP) method to overcome these challenges. The AbC G4-ChIP achieves (i) minimized in vitro artifacts during the incubation steps, and (ii) capture of G4-quadruplexes which are not protein-bound. We have applied the AbC G4-ChIP to study the regulatory effect of a CGG-repeat binding protein CGGBP1 on G4-quadruplex formation. The AbC G4-ChIP identifies inter-strand G/C-skew as a sequence property associated with CGGBP1-regulated G4-quadruplexes.

2024-03-20 | GSE202456 | GEO

DNA G-quadruplexes contribute to CTCF and cohesin recruitment

Project description:G-quadruplex (G4) sites in the human genome frequently colocalize with CCCTC-binding factor (CTCF)-bound sites within topologically associating domains (TADs) or at TAD boundaries. We investigated three mechanisms by which G4s may contribute to CTCF recruitment. One involved direct interactions between CTCF and G4s that persisted in the G0/G1 phase of the cell cycle. Synthetic G4s from CpG islands (CGIs) formed complexes with CTCF in vitro, and CTCF occupancy at the respective sites in the genome was modulated by a G4-stabilizing ligand. Another possible mechanism was through G4 interference with DNA methyltransferase activity in CGIs. Bioinformatics analysis confirmed that G4s underlie the association between CTCF and CGIs, but did not support a critical role for methylation in CTCF recruitment to G4-harboring CGIs. The third mechanism was through attracting additional protein factors. We found that G4s are recognized by the nucleosome density modulating high-mobility group (HMG) proteins and the cohesin-interacting protein additional sex combs-like 1. The affinity for these proteins is the basis for indirect G4 contributions to CTCF positioning and TAD demarcation.

2021-04-23 | GSE173074 | GEO

Characterization of G-quadruplexes in the rice genome

Project description:DNA G-quadruplex (G4) is a non-canonical four-stranded nucleic acid structure functioning in various biological processes in mammals. G4 ChIP-seq assay, In this study, we developed a robust BG4-DNA ChIP-seq for global identification of DNA G4 in rice..We found that G4s harbored some functional motifs for binding of certain trans-factors, were co-localized with R-loops and DHSs in the rice genome. Importantly, G4s exhibited differential effects on DNA methylation between TE and non-TE genes in rice. Especially, G4 intensity-dependent enrichment occurred between DNA 5mC and 6mA.These DNA-related features suggest potential regulatory roles of G4 in rice. Thus, our study will pave the way for prompting intensive characterization towards identifying novel functions of G4 in plants, especially for agronomic important crops.

2021-07-01 | GSE132775 | GEO

Detection of genomic G-quadruplexes in living cells using a small artificial protein

Project description:G-quadruplex (G4) structures formed by guanine-rich nucleic acids are implicated in essential physiological and pathological processes and serve as important drug targets. The genome-wide detection of G4s in living cells is important for exploring the functional role of G4s but has not yet been achieved due to the lack of a suitable G4 probe. Here we report an artificial 6.7 kDa G4 probe (G4P) protein that binds G4s with high affinity and specificity. We used it to capture G4s in living human, mouse, and chicken cells with the ChIP-Seq technique, yielding genome-wide landscape as well as details on the positions, frequencies, and sequence identities of G4 formation in these cells. Our results indicate that transcription is accompanied by a robust formation of G4s in genes. In human cells, we detected up to >123,000 G4P peaks, of which >1/3 had a fold increase of ≥5 and were present in >60% promoters and ~70% genes. Being much smaller than a scFv antibody (27 kDa) or even a nanobody (12-15 kDa), we expect that the G4P may find diverse applications in biology, medicine, and molecular devices as a G4 affinity agent.

2020-10-13 | GSE133379 | GEO

DNA G-quadruplexes in human stem cells and during differentiation

Project description:The establishment of cell identity involves the activation of developmental gene expression programs and is underpinned by epigenetic factors including DNA methylation and histone modifications. G-quadruplex DNA secondary structures (G4) are genomic elements implicated in transcriptional regulation, genome instability and cancer. We reasoned that G4s might be central features that influence development. In human embryonic stem cells G4s are highly abundant and progressively lost during differentiation. They are prevalent in enhancers and promoters and their inheritance is linked to transcriptional stabilisation of key homeostasis genes and to transitions in the histone modification landscape. Interventional G4 stabilisation by a small molecule leads to developmental delay. Our findings suggest that G4s are epigenetic marks involved in stem cell pluripotency and differentiation.

2021-11-10 | GSE161531 | GEO

Identification of human proteins interacting with locked G4 structures

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

Co-immunoprecipitation of G-quadruplex-containing Core Promoter and nanoLC-FAMIS-MS/MS

Project description:G-quadruplexes (G4s) are noncanonical DNA secondary structures formed through the self-association of guanines, and they are distributed widely across the genome. G4 participates in multiple biological processes including gene transcription, and G4-targeted ligands serve as potential therapeutic agents for DNA-targeted therapies. However, genome-wide studies of the exact roles of G4s in transcriptional regulation are still lacking. We found that drug-induced promoter-proximal RNA polymerase II pausing promotes nearby G4 formation, and oppositely, G4 stabilization by G4-targeted ligands globally reduces RNA polymerase II occupancy at gene promoters as well as nascent RNA synthesis. To study the underlying mechanisms by which native G4 affects transcriptional regulation, we annealed the biotin-labeled core promoter DNA to form G4s and performed pull-down assays with nuclear extraction proteins in the presence or absence of TMPyP4. Mass spectrometry analysis was performed to identify the interacting proteins with G4-forming core promoter DNA.

2021-07-19 | PXD026830 | Pride

G-quadruplexes sense natural porphyrin metabolites for regulation of gene transcription and chromatin landscapes

Project description:G-quadruplexes (G4s) are unique noncanonical nucleic acid secondary structures, which could interact with transcription factors and chromatin remodelers to regulate cell type-specific transcriptome and shape chromatin landscapes. Based on the direct interactions between G4 and natural porphyrins, we established an in situ capture sequencing approach combining synthesized biotin-PEG4-Hemin and Cleavage Under Targets and Tagmentation (CUT&Tag) strategy to profile the Hemin binding sites in the human genome. We found that a proportion of G4s overlapped with Hemin binding sites and Hemin promoted genome-wide G4 formation at Hemin binding sites. Hemin treatments impaired gene transcription initiation and altered chromatin landscape with decreased H3K27ac and H3K4me3 modifications. Interestingly, G4 was not involved in the canonic Hemin-BACH1-NRF2-mediated enhancer activation process, highlighting an unprecedented G4-dependent mechanism for metabolic regulation of transcription. Furthermore, Hemin induced specific gene expression profiles in mouse primary hepatocytes, and block of Hemin degradation in mice by Hmox1 knockdown resulted in hepatic injury, providing in vivo insights for metabolic control of gene transcription by porphyrins.

2022-11-23 | GSE198658 | GEO

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