CpG and Non-CpG Methylation in Epigenetic Gene Regulation and Brain Function

Jang, Hyun Sik; Shin, Woo‐Ri; Lee, Jeong Eon; Tae, Jeong

doi:10.3390/genes8060148

Cited by 286 publications

(162 citation statements)

References 160 publications

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“…These epigenetic modifications can affect gene expression via environmental changes (16). DNA methylation is defined as the addition of a methyl group to a cytosine, usually in CpG islands (17). DNA methylation at CpG-rich promoters or gene regulatory regions is normally associated with the inhibition of gene expression (17).…”

Section: Introductionmentioning

confidence: 99%

A Maternal High-Fat Diet Induces DNA Methylation Changes That Contribute to Glucose Intolerance in Offspring

et al. 2019

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Scope:Overnutrition in utero is a critical contributor to the susceptibility of diabetes by programming, although the exact mechanism is not clear. In this paper, we aimed to study the long-term effect of a maternal high-fat (HF) diet on offspring through epigenetic modifications.Procedures: Five-week-old female C57BL6/J mice were fed a HF diet or control diet for 4 weeks before mating and throughout gestation and lactation. At postnatal week 3, pups continued to consume a HF or switched to a control diet for 5 weeks, resulting in four groups of offspring differing by their maternal and postweaning diets.Results: The maternal HF diet combined with the offspring HF diet caused hyperglycemia and insulin resistance in male pups. Even after changing to the control diet, male pups exposed to the maternal HF diet still exhibited hyperglycemia and glucose intolerance. The livers of pups exposed to a maternal HF diet had a hypermethylated insulin receptor substrate 2 (Irs2) gene and a hypomethylated mitogen-activated protein kinase kinase 4 (Map2k4) gene. Correspondingly, the expression of the Irs2 gene decreased and that of Map2k4 increased in pups exposed to a maternal HF diet.Conclusion: Maternal overnutrition programs long-term epigenetic modifications, namely, Irs2 and Map2k4 gene methylation in the offspring liver, which in turn predisposes the offspring to diabetes later in life.

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Section: Introductionmentioning

confidence: 99%

A Maternal High-Fat Diet Induces DNA Methylation Changes That Contribute to Glucose Intolerance in Offspring

et al. 2019

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“…However, non-CpG methylation appears to be restricted to a few specific cell types, notably neurons and glial cells. Non-CpG methylation in mammals is performed by DNMT3A and DNMT3B members of DNA methyltransferase enzyme family 41 .…”

Section: Cpc) Methylation Via Dnmt3amentioning

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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“…The observed CpG methylation pattern indicates that ALDH3B2 gene is active and its expression is controlled by an epigenetic mechanism. Depending on the location of CpG sites their hypermethylation can result in either increased (when located in a gene body) or decreased (when located in promoters or enhancers) gene expression [7].…”

Section: Introductionmentioning

confidence: 99%

Detection of ALDH3B2 in Human Placenta

Michorowska

Giebułtowicz

Wolinowska

et al. 2019

IJMS

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Aldehyde dehydrogenase 3B2 (ALDH3B2) gene contains a premature termination codon, which can be skipped or suppressed resulting in full-length protein expression. Alternatively, the longest putative open reading frame starting with the second in-frame start codon would encode short isoform. No unequivocal evidence of ALDH3B2 expression in healthy human tissues is available. The aim of this study was to confirm its expression in human placenta characterized by the highest ALDH3B2 mRNA abundance. ALDH3B2 DNA and mRNA were sequenced. The expression was investigated using western blot. The identity of the protein was confirmed using mass spectrometry (MS). The predicted tertiary and quaternary structures, subcellular localization, and phosphorylation sites were assessed using bioinformatic analyses. All DNA and mRNA isolates contained the premature stop codon. In western blot analyses, bands corresponding to the mass of full-length protein were detected. MS analysis led to the identification of two unique peptides, one of which is encoded by the nucleotide sequence located upstream the second start codon. Bioinformatic analyses suggest cytoplasmic localization and several phosphorylation sites. Despite premature stop codon in DNA and mRNA sequences, full-length ALDH3B2 was found. It can be formed as a result of premature stop codon readthrough, complex phenomenon enabling stop codon circumvention.

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CpG and Non-CpG Methylation in Epigenetic Gene Regulation and Brain Function

Cited by 286 publications

References 160 publications

A Maternal High-Fat Diet Induces DNA Methylation Changes That Contribute to Glucose Intolerance in Offspring

A Maternal High-Fat Diet Induces DNA Methylation Changes That Contribute to Glucose Intolerance in Offspring

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

Detection of ALDH3B2 in Human Placenta

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