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

Abstract

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...

How Can CpG Methylations, and Pair-to-Pair Correlations between the Main (Gene) and the Opposite Strands, Suggest a Bending DNA Loop: Insights into the 5′-UTR of DAT1

“…The present work is currently limited to a graphic representation of the inferences drawn by data as discussed above, which obviously would require in-depth verification. The idea that DNA may form loops is quite common; additionally, we may propose that short motifs exist to allow the formation of local secondary structures [8][9][10][11]. Once such looping secondary structures are in place, it is becoming increasingly evident that epigenetic regulations occur [12][13][14][15].…”

The i-Motif as a Molecular Target: More Than a Complementary DNA Secondary Structure

“…Selective serotonin reuptake inhibitors are commonly prescribed anti-depression and anti-psychotic medications, but cause severe adverse effects in certain patient populations [156]. As further potential for targeting the i-motif in various neurological disease states, epigenetic modifications that favor i-motif formation are hypothesized to contribute to synaptic plasticity and memory formation [157].…”