CpG Methylation Changes G-Quadruplex Structures Derived from Gene Promoters and Interaction with VEGF and SP1

Tsukakoshi, Kaori; Saito, Shiori; Yoshida, Wataru; Goto, Shinichi

doi:10.3390/molecules23040944

Cited by 35 publications

(30 citation statements)

References 55 publications

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“…Maps of DNMT1 chromatin binding sites and endogenous G4s in human K562 leukaemia cells identified using ChIP-seq and G4 ChIP-seq, respectively, revealed that at CpG islands most G4s occur where DNMT1 is bound, leading to a proposal that G4s regulate DNA methylation by sequestering DNMTs [84]. Conversely, DNA methylation can influence G4 topology [85] and may modulate binding by other G4-associated proteins. For instance, CpG methylation at the hTERT gene promoter was suggested to induce G4 formation, resulting in displacement of the CCCTC-binding factor (CTCF) and elevated transcription [86].…”

Section: Natural G4-binding Proteinsmentioning

confidence: 99%

The Structure and Function of DNA G-Quadruplexes

Spiegel

Adhikari

Balasubramanian

2020

Trends in Chemistry

639

568

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Guanine-rich DNA sequences can fold into four-stranded, noncanonical secondary structures called G-quadruplexes (G4s). G4s were initially considered a structural curiosity, but recent evidence suggests their involvement in key genome functions such as transcription, replication, genome stability, and epigenetic regulation, together with numerous connections to cancer biology. Collectively, these advances have stimulated research probing G4 mechanisms and consequent opportunities for therapeutic intervention. Here, we provide a perspective on the structure and function of G4s with an emphasis on key molecules and methodological advances that enable the study of G4 structures in human cells. We also critically examine recent mechanistic insights into G4 biology and protein interaction partners and highlight opportunities for drug discovery. Beyond the DNA Double HelixA chemist's perspective on the function of a molecule, or a system of molecules, is typically led by a consideration of how molecular structure dictates function. The most widely recognised DNA structure is that of the classical DNA double helix [1], which defines a structural basis for the genetic code via defined base-pairing. Yet, it is evident that DNA is structurally dynamic and capable of adopting alternative secondary structures. One such class of DNA secondary structure is the four-stranded Gquadruplex (G4). Herein, we discuss some of the key scientific history that has shaped our understanding of this structural motif, its probable functions in biology, and major unanswered questions that remain to be solved.

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Section: Natural G4-binding Proteinsmentioning

confidence: 99%

The Structure and Function of DNA G-Quadruplexes

Spiegel

Adhikari

Balasubramanian

2020

Trends in Chemistry

639

568

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Section: G4 and Methylationmentioning

confidence: 99%

Hypothesis: Regulation of neuroplasticity may involve I-motif and G-quadruplex DNA formation modulated by epigenetic mechanisms

Todorov

Cunha

2019

Medical Hypotheses

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Recent studies demonstrated the existence in vivo of various functional DNA structures that differ from the double helix. The G-quadruplex (G4) and intercalated motif (I-motif or IM) DNA structures are formed as knots where, correspondingly, guanines or cytosines on the same strand of DNA bind to each other. There are grounds to believe that G4 and IM sequences play a significant role in regulating gene expression considering their tendency to be found in or near regulatory sites (such as promoters, enhancers, and telomeres) as well as the correlation between the prevalence of G4 or IM conformations and specific phases of cell cycle. Notably, G4 and IM capable sequences tend to be found on the opposite strands of the same DNA site with at most one of the two structures formed at any given time. The recent evidence that K + , Mg 2+ concentrations directly affect IM formation (and likely G4 formation indirectly) lead us to believe that these structures may play a major role in synaptic plasticity of neurons, and, therefore, in a variety of central nervous system (CNS) functions including memory, learning, habitual behaviors, pain perception and others. Furthermore, epigenetic mechanisms, which have an important role in synaptic plasticity and memory formation, were also shown to influence formation and stability of G4s and IMs. Our hypothesis is that non-canonical DNA and RNA structures could be an integral part of neuroplasticity control via gene expression regulation at the level of transcription, translation and splicing. We propose that the regulatory activity of DNA IM and G4 structures is modulated by DNA methylation/demethylation of the IM and/or G4 sequences, which facilitates the switch between canonical and non-canonical conformation. Other neuronal mechanisms interacting with the formation and regulatory activity of non-canonical DNA and RNA structures, particularly G4, IM and triplexes, may involve microRNAs as well as ion and proton fluxes. We are proposing experiments in acute brain slices and in vivo to test our hypothesis. The proposed studies would provide new insights into fundamental neuronal mechanisms in health and disease and potentially open new avenues for treating mental health disorders. I-motif and G-quadruplexWhile double helix DNA structure (B-form) is the most common conformation, a variety of other forms are known to exist in vitro 1-5 . Some forms also appear to exist in vivo and were shown to have physiological significance 6 . Of those, G-quadruplex (G4) and intercalated motif (I-motif or IM) appear to be the most interesting. G4 is found in G-rich regulatory regions of the genome and was demonstrated to exist in vivo in several studies 6,7 . There is also evidence of its involvement in regulatory pathways 8 .IM, a form occurring primarily in C-rich regulatory regions and are characterized by C:C+ pairs. Hence IMs form more easily at lower pH. However, IMs can form at normal pH and are also affected by other factors, including ionic strengths (K + , Mg 2+ concentration in particula...

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“…Methylation appears to affect the formation and stability of G4 and thereby modulate the effect of G4-capable sequences on transcription regulation 12,13 . Tsukakoshi and colleagues found that the binding of the transcription factor SP1 to the G4-forming DNA sequence in the promoter of VEGF gene can be altered by CpG methylation.…”

Section: G4 and Methylationmentioning

confidence: 99%

“…This may occur in one of the following ways: Similar methylation-related effects may be expected for G4. For example, CpG methylation appears to affect G4 stability and transcription factor binding to VEGF promoter 12 .…”

Section: Hypothesis: the Regulatory Effects Of Dna Methylation On Neumentioning

confidence: 99%

Hypothesis: Regulation of neuroplasticity may involve I-motif and G-quadruplex DNA formation modulated by epigenetic mechanisms

Todorov¹,

Cunha

2018

Preprint

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Recent studies demonstrated the existence in vivo of various functional DNA structures that differ from the double helix. The G-quadruplex (G4) and intercalated motif (I-motif or IM) DNA structures are formed as knots where, correspondingly, guanines or cytosines on the same strand of DNA bind to each other. There are grounds to believe that G4 and IM sequences play a significant role in regulating gene expression considering their tendency to be found in or near regulatory sites (such as promoters, enhancers, and telomeres) as well as the correlation between the prevalence of G4 or IM conformations and specific phases of cell cycle. Notably, G4 and IM capable sequences tend to be found on the opposite strands of the same DNA site with at most one of the two structures formed at any given time. The recent evidence that K+, Mg2+ concentrations directly affect IM formation (and likely G4 formation indirectly) lead us to believe that these structures may play a major role in synaptic plasticity of neurons, and, therefore, in a variety of central nervous system (CNS) functions including memory, learning, habitual behaviors, pain perception and others. Furthermore, epigenetic mechanisms, which have an important role in synaptic plasticity and memory formation, were also shown to influence formation and stability of G4s and IMs. Our hypothesis is that non-canonical DNA and RNA structures could be an integral part of neuroplasticity control via gene expression regulation at the level of transcription, translation and splicing. We propose that the regulatory activity of DNA IM and G4 structures is modulated by DNA methylation/demethylation of the IM and/or G4 sequences, which facilitates the switch between canonical and non-canonical conformation. Other neuronal mechanisms interacting with the formation and regulatory activity of non-canonical DNA and RNA structures, particularly G4, IM and triplexes, may involve microRNAs as well as ion and proton fluxes. We are proposing experiments in acute brain slices and in vivo to test our hypothesis. The proposed studies would provide new insights into fundamental neuronal mechanisms in health and disease and potentially open new avenues for treating mental health disorders.

show abstract

CpG Methylation Changes G-Quadruplex Structures Derived from Gene Promoters and Interaction with VEGF and SP1

Cited by 35 publications

References 55 publications

The Structure and Function of DNA G-Quadruplexes

The Structure and Function of DNA G-Quadruplexes

Hypothesis: Regulation of neuroplasticity may involve I-motif and G-quadruplex DNA formation modulated by epigenetic mechanisms

Hypothesis: Regulation of neuroplasticity may involve I-motif and G-quadruplex DNA formation modulated by epigenetic mechanisms

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