Genome-wide Mapping of Endogenous G-quadruplexes Unravels Their Roles in Enhancer Architecture across Human Cell Lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE234054 | GEO | 2024/05/01
REPOSITORIES: GEO
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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.
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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.
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Project description:We report here on G4RP-seq, which comprises of a cross-linking step, followed by chemical-affinity capture with the G4-specific small-molecule, BioTASQ and target identification using sequencing. This allows for capturing global snapshots of relative average levels of transiently folded G4-RNAs. We observed widespread G4-RNA targets indicative of transient G4 formation in several RNA entities in living human cells. G4RP-seq has also demonstrated that G4-stabilizing ligands (BRACO-19 and RHPS4) can change the G4 transcriptomic landscape, most notably in long non-coding RNAs. G4RP-seq thus provides a proof-of-principle for studying the G4-RNA landscape, as well as new ways of considering the mechanisms underlying G4-RNA formation and the activity of G4-stabilizing ligands.
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Project description:Characteristic features of chromatin states are not limited to particular epigenetic modifications but include other regulatory cues, such as linker DNA length, typically ranging from around 35-55 bp in most eu- and heterochromatin domains (Valouev et al, 2011; Voong et al., 2016, Cell) to over 200 bp in nucleosome-depleted regions (NDRs) found at active enhancers and promoters (Schones et al, 2008; Hansen He et al, 2010). To investigate whether and how nucleosome linker DNA affects chromatin recognition by nuclear proteins we performed an additional set of affinity purifications using di-nucleosomes incorporating different DNA linkers. Here, we investigated the effect of a 200 bp di-nucleosome linker DNA represented by scrambled DNA or SV40 enhancer DNA sequence on the nuclear protein binding to di-nucleosome decorated with enhancer-associated modifications, including H3K4me1 and H3K27ac.
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Project description:Glucocorticoid hormone plays a major role in metabolism and many related diseases. The hormone-bound glucocorticoid receptor (GR) binds to a specific set of enhancers in different cell types, resulting in unique patterns of gene expression. GR-responsive enhancers have an accessible chromatin structure prior to hormone treatment (“pre-programmed”), whereas unresponsive enhancers specific to other cell types are inaccessible and inactive. Here we have addressed the role of chromatin structure in cell-specific GR-enhancer programming by precise mapping of nucleosome positions in mouse adenocarcinoma cells. We show that, before hormone treatment, some pre-programmed GR-enhancers are nucleosome-depleted, associated with the Brg1 chromatin remodeler and flanked by nucleosomes exchanging histones H2A.Z and H2A. However, most pre-programmed GR-enhancers are assembled into a nucleosome that exchanges H2A.Z and H2A, with little or no Brg1. After hormone treatment, nucleosomes at both types of pre-programmed GR-enhancer shift apart, coinciding with increased levels of Brg1, and continue to exchange H2A.Z and H2A. Hormone removal rapidly reverses these nucleosome shifts. In contrast, inactive GR-enhancers are nucleosomal, lack Brg1, do not exchange H2A.Z or H2A and do not respond to hormone. Thus, pre-programmed GR-enhancers are marked by a dynamic, mutable chromatin structure characterized by high levels of H2A.Z exchange. We propose that nucleosome-depleted GR-enhancers result from the binding of other transcription factors together with Brg1 to assist loading of GR after hormone treatment. At nucleosomal enhancers, GR binding may be directly facilitated by increased transient exposure of enhancer DNA associated with H2A.Z exchange.
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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.
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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.
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Project description:We investigated herein the interaction between nucleolin (NCL) and a set of G4 sequences derived from the CEB25 human minisatellite which adopt a parallel topology while differing by the length of the central loop (from 9nt to1nt). It is revealed that NCL strongly binds to long-loop (9-5 nt) G4 whilst interacting weakly with the shorter variants (loop < 3nt). Photocrosslinking experiments using 5-bromouracil (BrdU) modified sequences further confirmed the loop-length dependency thereby indicating that the CEB25-WT (9nt) is the best G4 substrate. Quantitative proteomic analysis (LC-MS/MS) of the photocrosslinking product(s) obtained with NCL bound to this sequence enabled the identification of one contact site within the 9nt loop. The protein fragment identified is located in the helix of the RBD2 domain of NCL, shedding light on the role of this structural element in the G4-loop recognition. Then, the ability of a panel of benchmark G4 ligands to prevent the NCL/G4 interaction was explored. It was found that only the most potent ligand PhenDC3 is able to inhibit NCL binding, thereby suggesting that the terminal guanine quartet is also a strong determinant of G4 recognition, putatively through interaction with the RGG domain. This study puts forward the molecular mechanism by which NCL recognizes G4-containing long loops and leads to propose a model implying a concerted action of RBD2 and RGG domains to achieve specific G4 recognition via a dual loop-quartet interaction.
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Project description:Single-stranded DNA or RNA sequences rich in guanine (G) can adopt non-canonical structures known as G-quadruplexes (G4). G4 in the mitochondrial genome are heavy-strand enriched and have been associated with the formation of deletion breakpoints that cause mitochondrial diseases. However, the functional role of G4 structures in mitochondria remains unclear. Here, we have identified RHPS4 as a G4-specific ligand that localizes to mitochondria and causes replication pausing, with mitochondrial DNA (mtDNA) depletion occurring at higher dosage. We further show that RHPS4 interferes with mitochondrial transcript elongation at low doses, leading to respiratory complex depletion. These unprecedented observations suggest that G4 motifs modulate mitochondrial transcription and replication efficiency. Using the differential effects of high vs low RHPS4 dosing, we characterized gene expression pathway responses to mitochondrial transcription inhibition or mitochondrial genome depletion. Importantly, a human mtDNA mutation that increases G4 formation potential strongly enhanced the RHPS4-mediated mitochondrial respiratory defect. We propose that abnormal G4 dynamics may contribute to mtDNA instability and gene expression defects, particularly in the presence of mitochondrial mutations that enhance the G4 formation.
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Project description:We report the RNA-seq data for rat nucleus pulposus cells after stabilizing G-Quadruplexes (G4). We sequenced rat nucleus pulposus cells treated with PDS, Braco-19 and Phen-DC3 separately and untreated with these G4 stabilizers, which could stabilize G4 structure in cells.
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