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  • Journal article
    Di Antonio M, 2024,

    The emerging roles of multimolecular G-quadruplexes in transcriptional regulation and chromatin organization

    , Accounts of Chemical Research, ISSN: 0001-4842

    Conspectus: The ability of genomic DNA to adopt non-canonical, secondary structures known as G-quadruplexes (G4s) under physiological conditions has been recognized for its potential regulatory function of various biological processes. Amongst those, transcription has recently emerged as a key process that can be heavily affected by G4 formation, particularly when these structures form at gene promoters. Whilst the presence of G4s within gene promoters has been traditionally associated with transcriptional inhibition, in a model whereby G4s act as roadblocks to polymerase elongation, recent genomics experiments have revealed that the regulatory role of G4s in transcription is more complex than initially anticipated. Indeed, earlier studies linking G4-formation and transcription mainly relied on small-molecule ligands to stabilize and promote G4s, which might lead to disruption of protein-DNA interactions and local environments and, therefore, not necessarily reflect the endogenous function of G4s at gene promoters. There is now strong evidence pointing towards G4s being associated with transcriptional enhancement, rather than repression, through multifaceted mechanisms such as recruitment of key transcriptional proteins, molding of chromatin architecture, and initiation of phase separation events.In this Account, we explore pivotal findings from our research on a particular subset of G4s, namely those formed through interactions between distant genomic locations or independent nucleic acid strands, referred to as multimolecular G4s (mG4s), and their active role in transcriptional regulation. We will present our recent studies suggesting that the formation of mG4s may positively regulate transcription by inducing phase-separation events and selectively recruiting chromatin-remodeling proteins. Our work highlighted how mG4-forming DNA and RNA sequences can lead to liquid-liquid phase separation (LLPS) in the absence of any protein. This discovery provided new insights
  • Journal article
    Fabrini G, Farag N, Nuccio SP, Li S, Stewart JM, Tang AA, McCoy R, Owens RM, Rothemund PWK, Franco E, Di Antonio M, Di Michele Let al., 2024,

    Co-transcriptional production of programmable RNA condensates and synthetic organelles.

    , Nat Nanotechnol

    Condensation of RNA and proteins is central to cellular functions, and the ability to program it would be valuable in synthetic biology and synthetic cell science. Here we introduce a modular platform for engineering synthetic RNA condensates from tailor-made, branched RNA nanostructures that fold and assemble co-transcriptionally. Up to three orthogonal condensates can form simultaneously and selectively accumulate fluorophores through embedded fluorescent light-up aptamers. The RNA condensates can be expressed within synthetic cells to produce membrane-less organelles with a controlled number and relative size, and showing the ability to capture proteins using selective protein-binding aptamers. The affinity between otherwise orthogonal nanostructures can be modulated by introducing dedicated linker constructs, enabling the production of bi-phasic RNA condensates with a prescribed degree of interphase mixing and diverse morphologies. The in situ expression of programmable RNA condensates could underpin the spatial organization of functionalities in both biological and synthetic cells.
  • Journal article
    Galli S, Flint G, Ruzickova L, Di Antonio Met al., 2024,

    Genome-wide mapping of G-quadruplex DNA: a step-by-step guide to select the most effective method

    , RSC Chemical Biology, Vol: 5, Pages: 426-438, ISSN: 2633-0679

    The development of methods that enabled genome-wide mapping of DNA G-quadruplex structures in chromatin has played a critical role in providing evidence to support the formation of these structures in living cells. Over the past decade, a variety of methods aimed at mapping G-quadruplexes have been reported in the literature. In this critical review, we have sought to provide a technical overview on the relative strengths and weaknesses of the genomics approaches currently available, offering step-by-step guidance to assessing experimental needs and selecting the most appropriate method to achieve effective genome-wide mapping of DNA G-quadruplexes.
  • Journal article
    Robinson J, Stenspil SG, Maleckaite K, Bartlett M, Di Antonio M, Vilar R, Kuimova MKet al., 2024,

    Cellular visualization of G-quadruplex RNA via fluorescence- lifetime imaging microscopy

    , Journal of the American Chemical Society, Vol: 146, Pages: 1009-1018, ISSN: 0002-7863

    Over the past decade, appreciation of the roles of G-quadruplex (G4) structures in cellular regulation and maintenance has rapidly grown, making the establishment of robust methods to visualize G4s increasingly important. Fluorescent probes are commonly used for G4 detection in vitro; however, achieving sufficient selectivity to detect G4s in a dense and structurally diverse cellular environment is challenging. The use of fluorescent probes for G4 detection is further complicated by variations of probe uptake into cells, which may affect fluorescence intensity independently of G4 abundance. In this work, we report an alternative small-molecule approach to visualize G4s that does not rely on fluorescence intensity switch-on and, thus, does not require the use of molecules with exclusive G4 binding selectivity. Specifically, we have developed a novel thiazole orange derivative, TOR-G4, that exhibits a unique fluorescence lifetime when bound to G4s compared to other structures, allowing G4 binding to be sensitively distinguished from non-G4 binding, independent of the local probe concentration. Furthermore, TOR-G4 primarily colocalizes with RNA in the cytoplasm and nucleoli of cells, making it the first lifetime-based probe validated for exploring the emerging roles of RNA G4s in cellulo.
  • Book chapter
    Balcerowicz M, Wigge PA, Di Antonio M, Chung Bet al., 2024,

    Monitoring Real-Time Temperature Dynamics of a Short RNA Hairpin Using Förster Resonance Energy Transfer and Circular Dichroism.

    , Pages: 149-158

    RNA molecules play crucial roles in gene expression regulation and cellular signaling, and these functions are governed by the formation of RNA secondary and tertiary structures. These structures are highly dynamic and subject to rapid changes in response to environmental cues, temperature in particular. Thermosensitive RNA secondary structures have been harnessed by multiple organisms to survey their temperature environment and to adjust gene expression accordingly. It is thus highly desirable to observe RNA structural changes in real time over a range of temperatures. Multiple approaches have been developed to study structural dynamics, but many of these require extensive processing of the RNA, large amounts of RNA input, and/or cannot be applied under physiological conditions. Here, we describe the use of a dually fluorescently labeled RNA oligonucleotide (containing a predicted hairpin structure) to monitor subtle RNA structural dynamics in vitro by Förster resonance energy transfer (FRET) and circular dichroism (CD) spectroscopy. These approaches can be employed under physiologically relevant conditions over a range of temperatures and with RNA concentrations as low as 200 nM; they enable us to observe RNA structural dynamics in real time and to correlate these dynamics with changes in biological processes such as translation.
  • Journal article
    Raguseo F, Wang Y, Li J, Petrić Howe M, Balendra R, Huyghebaert A, Vadukul DM, Tanase DA, Maher TE, Malouf L, Rubio-Sánchez R, Aprile FA, Elani Y, Patani R, Di Michele L, Di Antonio Met al., 2023,

    The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

    , Nature Communications, Vol: 14, ISSN: 2041-1723

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD.
  • Journal article
    Williams SL, Casas-Delucchi CS, Raguseo F, Guneri D, Li Y, Minamino M, Fletcher EE, Yeeles JTP, Keyser UF, Waller ZAE, Di Antonio M, Coster Get al., 2023,

    Replication-induced DNA secondary structures drive fork uncoupling and breakage

    , EMBO JOURNAL, Vol: 42, ISSN: 0261-4189
  • Journal article
    Monti L, Di Antonio M, 2023,

    G-Quadruplexes as Key Transcriptional Regulators in Neglected Trypanosomatid Parasites

    , CHEMBIOCHEM, Vol: 24, ISSN: 1439-4227
  • Journal article
    Baron L, Hadjerci J, Thoidingjam L, Plays M, Bucci R, Morris N, Muller S, Sindikubwabo F, Solier S, Caneque T, Colombeau L, Blouin CM, Lamaze C, Puisieux A, Bono Y, Gaillet C, Laraia L, Vauzeilles B, Taran F, Papot S, Karoyan P, Duval R, Mahuteau-Betzer F, Arimondo P, Cariou K, Guichard G, Micouin L, Etheve-Quelquejeu M, Verga D, Versini A, Gasser G, Tang C, Belmont P, Linkermann A, Bonfio C, Gillingham D, Poulsen T, Di Antonio M, Lopez M, Guianvarc'h D, Thomas C, Masson G, Gautier A, Johannes L, Rodriguez Ret al., 2023,

    PSL Chemical Biology Symposia Third Edition: A Branch of Science in its Explosive Phase

    , CHEMBIOCHEM, ISSN: 1439-4227
  • Journal article
    Liano D, Monti L, Chowdhury S, Raguseo F, Di Antonio Met al., 2022,

    Long-range DNA interactions: inter-molecular G-quadruplexes and their potential biological relevance

    , CHEMICAL COMMUNICATIONS, Vol: 58, Pages: 12753-12762, ISSN: 1359-7345
  • Journal article
    Rauchhaus J, Robinson J, Monti L, Di Antonio Met al., 2022,

    G-quadruplexes mark sites of methylation instability associated with ageing and cancer

    , Genes, Vol: 13, Pages: 1-11, ISSN: 2073-4425

    Regulation of the epigenome is critical for healthy cell function but can become disrupted with age, leading to aberrant epigenetic profiles including altered DNA methylation. Recent studies have indicated that DNA methylation homeostasis can be compromised by the formation of DNA secondary structures known as G-quadruplexes (G4s), which form in guanine-rich regions of the genome. G4s can be recognised and bound by certain methylation-regulating enzymes, and in turn perturb the surrounding methylation architecture. However, the effect G4 formation has on DNA 20methylation at critical epigenetic sites, remains elusive and poorly explored. In this work, we investigate the association between G4 sequences and prominent DNA methylation sites, termed ‘ageing clocks’, that act as bona fide dysregulated regions in aged and cancerous cells. Using a combination of in vitro (G4-seq) and in cellulo (BG4-ChIP) G4 distribution maps, we show that ageing clocks sites are significantly enriched with G4-forming sequences. The observed enrichment also varies across species and cell lines, being least significant in healthy cells and more pronounced in tumorigenic cells. Overall, our results suggest a biological significance of G4s in the realm of DNA methylation, which may be important for further deciphering the driving forces of diseases characterised by epigenetic abnormality, including ageing.
  • Journal article
    Chowdhury S, Wang J, Nuccio SP, Mao H, Di Antonio Met al., 2022,

    Short LNA-modified oligonucleotide probes as efficient disruptors of DNA G-quadruplexes

    , Nucleic Acids Research, Vol: 50, Pages: 7247-7259, ISSN: 0305-1048

    G-quadruplexes (G4s) are well known non-canonical DNA secondary structures that can form in human cells. Most of the tools available to investigate G4-biology rely on small molecule ligands that stabilise these structures. However, the development of probes that disrupt G4s is equally important to study their biology. In this study, we investigated the disruption of G4s using Locked Nucleic Acids (LNA) as invader probes. We demonstrated that strategic positioning of LNA-modifications within short oligonucleotides (10 nts.) can significantly accelerate the rate of G4-disruption. Single-molecule experiments revealed that short LNA-probes can promote disruption of G4s with mechanical stability sufficient to stall polymerases. We corroborated this using a single-step extension assay, revealing that short LNA-probes can relieve replication dependent polymerase-stalling at G4 sites. We further demonstrated the potential of such LNA-based probes to study G4-biology in cells. By using a dual-luciferase assay, we found that short LNA probes can enhance the expression of c-KIT to levels similar to those observed when the c-KIT promoter is mutated to prevent the formation of the c-KIT1 G4. Collectively, our data suggest a potential use of rationally designed LNA-modified oligonucleotides as an accessible chemical-biology tool for disrupting individual G4s and interrogating their biological functions in cells.
  • Journal article
    Fabrini G, Minard A, Brady R, Di Antonio M, Di Michele Let al., 2022,

    Cation-responsive and photocleavable hydrogels from non-canonical amphiphilic DNA nanostructures

    , Nano Letters: a journal dedicated to nanoscience and nanotechnology, Vol: 22, Pages: 602-611, ISSN: 1530-6984

    Thanks to its biocompatibility, versatility and programmable interactions, DNA has been proposed as a building block for functional, stimuli-responsive frameworks with applications in biosensing, tissue engineering and drug delivery. Of particular importance for in vivo applications is the possibility of making such nano-materials responsive to physiological stimuli. Here we demonstrate how combining non-canonical DNA G-quadruplex (G4) structures with amphiphilic DNA constructs yields nanos-tructures, which we termed “Quad-Stars”, capable of assembling into responsive hydrogel particles via a straightforward, enzyme-free, one-pot reaction. The embedded G4 structures allow one to trigger and control the assembly/disassembly in a reversible fashion by adding or removing K+ ions. Furthermore, the hydrogel aggregates can be photo disassembled upon near-UV irradiation in the presence of a porphyrin photosensitiser. The combinedreversibility of assembly, responsiveness and cargo-loading capabilities of the hydrophobic moieties make Quad-Stars a promising candidate for biosensors and responsive drug delivery carriers.
  • Journal article
    Liano D, Chowdhury S, Di Antonio M, 2021,

    Cockayne Syndrome B protein selectively interacts and resolves intermolecular DNA G-quadruplex structures.

    , Journal of the American Chemical Society, Vol: 143, Pages: 20988-21002, ISSN: 0002-7863

    Guanine-rich DNA can fold into secondary structures known as G-quadruplexes (G4s). G4s can form from a single DNA strand (intramolecular) or from multiple DNA strands (intermolecular), but studies on their biological functions have been often limited to intramolecular G4s, owing to the low probability of intermolecular G4s to form within genomic DNA. Herein, we report the first example of an endogenous protein, Cockayne Syndrome B (CSB), that can bind selectively with picomolar affinity toward intermolecular G4s formed within rDNA while displaying negligible binding toward intramolecular structures. We observed that CSB can selectively resolve intermolecular over intramolecular G4s, demonstrating that its selectivity toward intermolecular structures is also reflected at the resolvase level. Immunostaining of G4s with the antibody BG4 in CSB-impaired cells (CS1AN) revealed that G4-staining in the nucleolus of these cells can be abrogated by transfection of viable CSB, suggesting that intermolecular G4s can be formed within rDNA and act as binding substrate for CSB. Given that loss of function of CSB elicits premature aging phenotypes, our findings indicate that the interaction between CSB and intermolecular G4s in rDNA could be of relevance to maintain cellular homeostasis.
  • Journal article
    Di Antonio M, Robinson J, Raguseo F, Nuccio S, Liano Det al., 2021,

    DNA G-quadruplex structures: more than simple roadblocks to transcription?

    , Nucleic Acids Research, Vol: 49, Pages: 8419-8431, ISSN: 0305-1048

    It has been >20 years since the formation of G-quadruplex (G4) secondary structures in gene promoters was first linked to the regulation of gene expression. Since then, the development of small molecules to selectively target G4s and their cellular application have contributed to an improved understanding of how G4s regulate transcription. One model that arose from this work placed these non-canonical DNA structures as repressors of transcription by preventing polymerase processivity. Although a considerable number of studies have recently provided sufficient evidence to reconsider this simplistic model, there is still a misrepresentation of G4s as transcriptional roadblocks. In this review, we will challenge this model depicting G4s as simple ‘off switches’ for gene expression by articulating how their formation has the potential to alter gene expression at many different levels, acting as a key regulatory element perturbing the nature of epigenetic marks and chromatin architecture.
  • Journal article
    Di Antonio M, Overkleeft H, Wang C, Rulka Aet al., 2021,

    Outstanding Reviewers for <i>RSC Chemical Biology</i> in 2020

    , RSC CHEMICAL BIOLOGY, Vol: 2, Pages: 684-684, ISSN: 2633-0679
  • Journal article
    Balcerowicz M, Di Antonio M, Chung BYW, 2021,

    Monitoring real-time temperature dynamics of a short RNA hairpin using Förster resonance energy transfer and Circular Dichroism

    , Bio-protocol, Vol: 11

    RNA secondary structures are highly dynamic and subject to prompt changes in response to the environment. Temperature in particular has a strong impact on RNA structural conformation, and temperature-sensitive RNA hairpin structures have been exploited by multiple organisms to modify the rate of translation in response to temperature changes. Observing RNA structural changes in real-time over a range of temperatures is therefore highly desirable. A variety of approaches exists that probe RNA secondary structures, but many of these either require large amount and/or extensive processing of the RNA or cannot be applied under physiological conditions, rendering the observation of structural dynamics over a range of temperatures difficult. Here, we describe the use of a dually fluorescently labelled RNA oligonucleotide (containing the predicted hairpin structure) that can be used to monitor subtle RNA-structural dynamics by Förster Resonance Energy Transfer (FRET) at different temperatures with RNA concentration as low as 200 nM. FRET efficiency varies as a function of the fluorophores' distance; high efficiency can thus be correlated to a stable hairpin structure, whilst a reduction in FRET efficiency reflects a partial opening of the hairpin or a destabilisation of this structure. The same RNA sequence can also be used for Circular Dichroism spectroscopy to observe global changes of RNA secondary structure at a given temperature. The combination of these approaches allowed us to monitor RNA structural dynamics over a range of temperatures in real-time and correlate structural changes to plant biology phenotypes.
  • Journal article
    Di Antonio M, Ponjavic A, Radzevičius A, Ranasinghe RT, Catalano M, Zhang X, Shen J, Needham L-M, Lee SF, Klenerman D, Balasubramanian Set al., 2020,

    Single-molecule visualization of DNA G-quadruplex formation in live cells.

    , Nature Chemistry, Vol: 12, Pages: 832-837, ISSN: 1755-4330

    Substantial evidence now exists to support that formation of DNA G-quadruplexes (G4s) is coupled to altered gene expression. However, approaches that allow us to probe G4s in living cells without perturbing their folding dynamics are required to understand their biological roles in greater detail. Herein, we report a G4-specific fluorescent probe (SiR-PyPDS) that enables single-molecule and real-time detection of individual G4 structures in living cells. Live-cell single-molecule fluorescence imaging of G4s was carried out under conditions that use low concentrations of SiR-PyPDS (20 nM) to provide informative measurements representative of the population of G4s in living cells, without globally perturbing G4 formation and dynamics. Single-molecule fluorescence imaging and time-dependent chemical trapping of unfolded G4s in living cells reveal that G4s fluctuate between folded and unfolded states. We also demonstrate that G4 formation in live cells is cell-cycle-dependent and disrupted by chemical inhibition of transcription and replication. Our observations provide robust evidence in support of dynamic G4 formation in living cells.
  • Journal article
    Minard A, Morgan D, Raguseo F, Di Porzio A, Liano D, Jamieson AG, Di Antonio Met al., 2020,

    A short peptide that preferentially binds c-MYC G-quadruplex DNA

    , CHEMICAL COMMUNICATIONS, Vol: 56, Pages: 8940-8943, ISSN: 1359-7345
  • Journal article
    Chung BYW, Balcerowicz M, Di Antonio M, Jaeger KE, Geng F, Franaszek K, Marriott P, Brierley I, Firth AE, Wigge PAet al., 2020,

    An RNA thermoswitch regulates daytime growth in <i>Arabidopsis</i>

    , NATURE PLANTS, Vol: 6, Pages: 522-+, ISSN: 2055-026X
  • Journal article
    Raguseo F, Chowdhury S, Minard A, Di Antonio Met al., 2020,

    Chemical-biology approaches to probe DNA and RNA G-quadruplex structures in the genome

    , CHEMICAL COMMUNICATIONS, Vol: 56, Pages: 1317-1324, ISSN: 1359-7345
  • Journal article
    Weber J, Bollepalli L, Belenguer AM, Di Antonio M, De Mitri N, Joseph J, Balasubramanian S, Hunter CA, Bohndiek SEet al., 2019,

    An Activatable Cancer-Targeted Hydrogen Peroxide Probe for Photoacoustic and Fluorescence Imaging

    , CANCER RESEARCH, Vol: 79, Pages: 5407-5417, ISSN: 0008-5472
  • Journal article
    Zyner KG, Mulhearn DS, Adhikari S, Cuesta SM, Di Antonio M, Erard N, Hannon GJ, Tannahill D, Balasubramanian Set al., 2019,

    Genetic interactions of G-quadruplexes in humans

    , ELIFE, Vol: 8, ISSN: 2050-084X
  • Journal article
    Di Antonio M, Minard A, Liano D, Wang Xet al., 2019,

    The unexplored potential of quinone methides in chemical biology

    , Bioorganic and Medicinal Chemistry, Vol: 27, Pages: 2298-2305, ISSN: 0968-0896

    Quinone methides (QMs) are transient reactive species that can be efficiently generated from stable precursors under a variety of biocompatible conditions. Due to their electrophilic nature, QMs have been widely explored as cross-linking agents of DNA and proteins under physiological conditions. However, QMs also have a diene character and can irreversibly react via Diels-Alder reaction with electron-rich dienophiles. This particular reactivity has been recently exploited to label biomolecules with fluorophores in living cells.QMs are characterised by two unique properties that make them ideal candidates for chemical biology applications: i) they can be efficiently generated in situ from very stable precursors by means of bio-orthogonal protocols ii) they are reversible cross-linking agents, making them suitable for “catch and release” target-enrichment experiments. Nevertheless, there are only few examples reported to date that truly take advantage of QMs unique chemistry in the context of chemical-biology assay development. In this review, we will examine the most relevant examples that illustrate the benefit of using QMs for chemical biology purposes and we will anticipate novel approaches to further their applications in biologically relevant contexts.
  • Journal article
    Marsico G, Chambers VS, Sahakyan AB, McCauley P, Boutell JM, Antonio MD, Balasubramanian Set al., 2019,

    Whole genome experimental maps of DNA G-quadruplexes in multiple species

    , Nucleic Acids Research, Vol: 47, Pages: 3862-3874, ISSN: 0305-1048

    Genomic maps of DNA G-quadruplexes (G4s) can help elucidate the roles that these secondary structures play in various organisms. Herein, we employ an improved version of a G-quadruplex sequencing method (G4-seq) to generate whole genome G4 maps for 12 species that include widely studied model organisms and also pathogens of clinical relevance. We identify G4 structures that form under physiological K+ conditions and also G4s that are stabilized by the G4-targeting small molecule pyridostatin (PDS). We discuss the various structural features of the experimentally observed G-quadruplexes (OQs), highlighting differences in their prevalence and enrichment across species. Our study describes diversity in sequence composition and genomic location for the OQs in the different species and reveals that the enrichment of OQs in gene promoters is particular to mammals such as mouse and human, among the species studied. The multi-species maps have been made publicly available as a resource to the research community. The maps can serve as blueprints for biological experiments in those model organisms, where G4 structures may play a role.
  • Journal article
    Sengar A, Vandana JJ, Chambers VS, Di Antonio M, Winnerdy FR, Balasubramanian S, Anh TPet al., 2019,

    Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter

    , NUCLEIC ACIDS RESEARCH, Vol: 47, Pages: 1564-1572, ISSN: 0305-1048
  • Journal article
    Mao S-Q, Ghanbarian AT, Spiegel J, Cuesta SM, Beraldi D, Di Antonio M, Marsico G, Hansel-Hertsch R, Tannahill D, Balasubramanian Set al., 2018,

    DNA G-quadruplex structures mold the DNA methylome

    , Nature Structural and Molecular Biology, Vol: 25, Pages: 951-957, ISSN: 1545-9985

    Control of DNA methylation level is critical for gene regulation, and the factors that govern hypomethylation at CpG islands (CGIs) are still being uncovered. Here, we provide evidence that G-quadruplex (G4) DNA secondary structures are genomic features that influence methylation at CGIs. We show that the presence of G4 structure is tightly associated with CGI hypomethylation in the human genome. Surprisingly, we find that these G4 sites are enriched for DNA methyltransferase 1 (DNMT1) occupancy, which is consistent with our biophysical observations that DNMT1 exhibits higher binding affinity for G4s as compared to duplex, hemi-methylated, or single-stranded DNA. The biochemical assays also show that the G4 structure itself, rather than sequence, inhibits DNMT1 enzymatic activity. Based on these data, we propose that G4 formation sequesters DNMT1 thereby protecting certain CGIs from methylation and inhibiting local methylation.
  • Journal article
    Greenfield JL, Evans EW, Di Nuzzo D, Di Antonio M, Friend RH, Nitschke JRet al., 2018,

    Unraveling Mechanisms of Chiral Induction in Double-Helical Metallopolymers

    , Journal of the American Chemical Society, Vol: 140, Pages: 10344-10353, ISSN: 0002-7863

    © 2018 American Chemical Society. Self-assembled helical polymers hold great promise as new functional materials, where helical handedness controls useful properties such as circularly polarized light emission or electron spin. The technique of subcomponent self-assembly can generate helical polymers from readily prepared monomers. Here we present three distinct strategies for chiral induction in double-helical metallopolymers prepared via subcomponent self-assembly: (1) employing an enantiopure monomer, (2) polymerization in a chiral solvent, (3) using an enantiopure initiating group. Kinetic and thermodynamic models were developed to describe the polymer growth mechanisms and quantify the strength of chiral induction, respectively. We found the degree of chiral induction to vary as a function of polymer length. Ordered, rod-like aggregates more than 70 nm long were also observed in the solid state. Our findings provide a basis to choose the most suitable method of chiral induction based on length, regiochemical, and stereochemical requirements, allowing stereochemical control to be established in easily accessible ways.
  • Journal article
    Sahakyan AB, Chambers VS, Marsico G, Santner T, Di Antonio M, Balasubramanian Set al., 2017,

    Machine learning model for sequence-driven DNA G-quadruplex formation

    , SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
  • Journal article
    Hansel-Hertsch R, Di Antonio M, Balasubramanian S, 2017,

    DNA G-quadruplexes in the human genome: detection, functions and therapeutic potential

    , NATURE REVIEWS MOLECULAR CELL BIOLOGY, Vol: 18, Pages: 279-284, ISSN: 1471-0072

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