Targeting DNA Methylation in the Adult Brain through Diet

Metabolism and nutrition have a significant role in epigenetic modifications such as DNA methylation, which can influence gene expression. Recently, it has been suggested that bioactive nutrients and gut microbiota can alter DNA methylation in the central nervous system (CNS) through the gut–brain axis, playing a crucial role in modulating CNS functions and, finally, behavior. Here, we will focus on the effect of metabolic signals in shaping brain DNA methylation during adulthood. We will provide an overview of potential interactions among diet, gastrointestinal microbiome and epigenetic alterations on brain methylation and behavior. In addition, the impact of different diet challenges on cytosine methylation dynamics in the adult brain will be discussed. Finally, we will explore new ways to modulate DNA hydroxymethylation, which is particularly abundant in neural tissue, through diet.

Download Full-text

Interplay between Metabolism, Nutrition and Epigenetics in Shaping Brain DNA Methylation, Neural Function and Behavior

Genes ◽

10.3390/genes11070742 ◽

2020 ◽

Vol 11 (7) ◽

pp. 742 ◽

Cited By ~ 1

Author(s):

Tommaso Pizzorusso ◽

Paola Tognini

Keyword(s):

Dna Methylation ◽

Cytosine Methylation ◽

Maternal Nutrition ◽

Adult Brain ◽

Neural Function ◽

Control Mechanisms ◽

Dna Hydroxymethylation ◽

And Behavior ◽

The Impact ◽

The Brain

Gene expression in the brain is dramatically regulated by a variety of stimuli. While the role of neural activity has been extensively studied, less is known about the effects of metabolism and nutrition on transcriptional control mechanisms in the brain. Extracellular signals are integrated at the chromatin level through dynamic modifications of epigenetic marks, which in turn fine-tune gene transcription. In the last twenty years, it has become clear that epigenetics plays a crucial role in modulating central nervous system functions and finally behavior. Here, we will focus on the effect of metabolic signals in shaping brain DNA methylation, both during development and adulthood. We will provide an overview of maternal nutrition effects on brain methylation and behavior in offspring. In addition, the impact of different diet challenges on cytosine methylation dynamics in the adult brain will be discussed. Finally, the possible role played by the metabolic status in modulating DNA hydroxymethylation, which is particularly abundant in neural tissue, will be considered.

Download Full-text

Dynamics of the Methylome and Transcriptome during the Regeneration of Rice

Epigenomes ◽

10.3390/epigenomes2030014 ◽

2018 ◽

Vol 2 (3) ◽

pp. 14 ◽

Cited By ~ 2

Author(s):

Fei-Man Hsu ◽

Moloya Gohain ◽

Archana Allishe ◽

Yan-Jiun Huang ◽

Jo-Ling Liao ◽

...

Keyword(s):

Dna Methylation ◽

Oryza Sativa ◽

Somaclonal Variation ◽

Cytosine Methylation ◽

Callus Formation ◽

Expression Profiles ◽

Close Association ◽

Global Methylation ◽

Regeneration Efficiency ◽

The Impact

Oryza sativa indica (cv. IR64) and Oryza sativa japonica (cv. TNG67) vary in their regeneration efficiency. Such variation may occur in response to cultural environments that induce somaclonal variation. Somaclonal variations may arise from epigenetic factors, such as DNA methylation. We hypothesized that somaclonal variation may be associated with the differential regeneration efficiency between IR64 and TNG67 through changes in DNA methylation. We generated the stage-associated methylome and transcriptome profiles of the embryo, induced calli, sub-cultured calli, and regenerated calli (including both successful and failed regeneration) of IR64 and TNG67. We found that stage-associated changes are evident by the increase in the cytosine methylation of all contexts upon induction and decline upon regeneration. These changes in the methylome are largely random, but a few regions are consistently targeted at the later stages of culture. The expression profiles showed a dominant tissue-specific difference between the embryo and the calli. A prominent cultivar-associated divide in the global methylation pattern was observed, and a subset of cultivar-associated differentially methylated regions also showed stage-associated changes, implying a close association between differential methylation and the regeneration programs of these two rice cultivars. Based on these findings, we speculate that the differential epigenetic regulation of stress response and developmental pathways may be coupled with genetic differences, ultimately leading to differential regeneration efficiency. The present study elucidates the impact of tissue culture on callus formation and delineates the impact of stage and cultivar to determine the dynamics of the methylome and transcriptome in culture.

Download Full-text

Insight from animal models of environmentally driven epigenetic changes in the developing and adult brain

Development and Psychopathology ◽

10.1017/s095457941600081x ◽

2016 ◽

Vol 28 (4pt2) ◽

pp. 1229-1243 ◽

Cited By ~ 16

Author(s):

Tiffany S. Doherty ◽

Tania L. Roth

Keyword(s):

Central Nervous System ◽

Animal Models ◽

Behavioral Outcomes ◽

Adult Brain ◽

Epigenetic Changes ◽

Behavioral Deficits ◽

The Central Nervous System ◽

Brain And Behavior ◽

And Behavior ◽

The Brain

AbstractThe efforts of many neuroscientists are directed toward understanding the appreciable plasticity of the brain and behavior. In recent years, epigenetics has become a core of this focus as a prime mechanistic candidate for behavioral modifications. Animal models have been instrumental in advancing our understanding of environmentally driven changes to the epigenome in the developing and adult brain. This review focuses mainly on such discoveries driven by adverse environments along with their associated behavioral outcomes. While much of the evidence discussed focuses on epigenetics within the central nervous system, several peripheral studies in humans who have experienced significant adversity are also highlighted. As we continue to unravel the link between epigenetics and phenotype, discerning the complexity and specificity of epigenetic changes induced by environments is an important step toward understanding optimal development and how to prevent or ameliorate behavioral deficits bred by disruptive environments.

Download Full-text

Dissecting drug and prognostic lncRNA signature mediated by DNA methylation and transcription factor in colon cancer

10.21203/rs.3.rs-23145/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jiayu Zhang ◽

Zhen Shen ◽

Zheyu Song ◽

Jian Luan ◽

Yezhou Li ◽

...

Keyword(s):

Dna Methylation ◽

Colon Cancer ◽

Drug Response ◽

Risk Model ◽

Negative Relationship ◽

Epigenetic Alterations ◽

Key Factors ◽

Motif Occurrence ◽

The Impact

Abstract Background: Colon cancer is still the most commonly diagnosed malignancy and leading cause of death worldwide. Apart from living habits, genetic and epigenetic changes are key factors to influence the risk of colon cancer. However, the impact of epigenetic alterations in non-coding RNAs and the consequences for colon cancer has not been fully characterized.Methods: We detected differential methylation sites (DMSs) in lncRNA promoters, and identified lncQTMs by association test. To investigate TF binding affected by DNA methylation, we characterized known TF motif occurrence among DMSs collected from MEME suit. We further combined methylome and transcriptome data to construct TF-methylation-lncRNA relationships. To study the role of lncRNAs in drug response, we used pharmacological and lncRNA profiles derived from CCLE and predict drug response by lncRNA expression level. We also used the combination of TF-methylation-lncRNA relationship to stratified patient survival information by a risk model.Results: DNA methylation display global hyper-methylation character in lncRNA promoters, and they tend to have negative relationship with the corresponding lncRNAs. Negative lncQTMs located near TSS have more significant and stronger correlation with the corresponding lncRNAs. Some lncRNAs mediated by the interplay between DNA methylation and TFs are proved markers for colon cancer. Typically, lncRNA CAHM, RP11-834C11.4 and LINC00460 are good predictors for 5 drug components (17-AAG, Sorafenib, TKI258, RAF265, Topotecan) in colon cancer. And we found HES1_cg24685006_RP4-728D4.2 and SREBF1_cg05372727_LINC00460 relationships are prognostic signatures for colon cancer.Conclusions: These findings suggested lncRNAs mediated by the interplay between DNA methylation and TFs are promising predictors for drug response, besides, combined TF-methylation-lncRNA can serve as prognostic signature for colon cancer.

Download Full-text

Neuroprotective Effect of Piracetam against Cocaine-Induced Neuro Epigenetic Modification of DNA Methylation in Astrocytes

Brain Sciences ◽

10.3390/brainsci10090611 ◽

2020 ◽

Vol 10 (9) ◽

pp. 611

Author(s):

Kalaiselvi Sivalingam ◽

Thangavel Samikkannu

Keyword(s):

Dna Methylation ◽

Nuclear Dna ◽

Epigenetic Modification ◽

Neuroprotective Effect ◽

Dna Methyltransferases ◽

Epigenetic Changes ◽

Nootropic Drug ◽

The Central Nervous System ◽

Tet Enzymes ◽

The Impact

Cocaine abuse is known to alter mitochondrial biogenesis and induce epigenetic modification linked with neuronal dysfunction. Cocaine-induced epigenetic modification of DNA methylation and the mitochondrial genome may affect mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), as epigenetic DNA methylation is key to maintaining genomic integrity in the central nervous system (CNS). However, the impact of cocaine-mediated epigenetic changes in astrocytes has not yet been elucidated. In this study, we explored the neuroprotective effect of piracetam against cocaine-induced epigenetic changes in DNA methylation in astrocytes. To study our hypothesis, we exposed human astrocytes to cocaine alone or in combination with the nootropic drug piracetam. We examined the expression of the DNA methyltransferases (DNMTs) DNMT-1, DNMT-3A, and DNMT-3B; global DNA methylation levels of 5-methycytosine (5-mC); and induction of ten–eleven translocation (TET) enzymes in astrocytes. In addition, we analyzed mtDNA methylation by targeted next-generation bisulfite sequencing. Our data provide evidence that cocaine impairs DNMT activity and thereby has impacts on mtDNA, which might contribute to the neurodegeneration observed in cocaine users. These effects might be at least partially prevented by piracetam, allowing neuronal function to be maintained.

Download Full-text

Contribution of Dysregulated DNA Methylation to Autoimmunity

International Journal of Molecular Sciences ◽

10.3390/ijms222111892 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11892

Author(s):

Samanta C. Funes ◽

Ayleen Fernández-Fierro ◽

Diego Rebolledo-Zelada ◽

Juan P. Mackern-Oberti ◽

Alexis M. Kalergis

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Epigenetic Modifications ◽

Epigenetic Mechanisms ◽

Epigenetic Alterations ◽

Development And Differentiation ◽

Differential Gene ◽

The Impact

Epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs are known regulators of gene expression and genomic stability in cell growth, development, and differentiation. Because epigenetic mechanisms can regulate several immune system elements, epigenetic alterations have been found in several autoimmune diseases. The purpose of this review is to discuss the epigenetic modifications, mainly DNA methylation, involved in autoimmune diseases in which T cells play a significant role. For example, Rheumatoid Arthritis and Systemic Lupus Erythematosus display differential gene methylation, mostly hypomethylated 5′-C-phosphate-G-3′ (CpG) sites that may associate with disease activity. However, a clear association between DNA methylation, gene expression, and disease pathogenesis must be demonstrated. A better understanding of the impact of epigenetic modifications on the onset of autoimmunity will contribute to the design of novel therapeutic approaches for these diseases.

Download Full-text

Experience-dependent tuning of early olfactory processing in the adult brain

10.1101/558734 ◽

2019 ◽

Author(s):

Christopher M. Jernigan ◽

Rachael Halby ◽

Richard C. Gerkin ◽

Irina Sinakevitch ◽

Fernando Locatelli ◽

...

Keyword(s):

Adult Brain ◽

Dependent Plasticity ◽

Naturally Occurring ◽

Olfactory Experience ◽

The Central Nervous System ◽

Response Profiles ◽

Olfactory Processing ◽

Multiple Levels ◽

Time Frames ◽

The Impact

AbstractExperience-dependent plasticity in the central nervous system allows an animal to adaptively change their responses to stimuli over different time scales. In this study we explored the different time frames and mechanisms over which olfactory experience-dependent plasticity works. We measured the impact of experience on early olfactory processing by comparing naturally foraging animals with a diverse olfactory experience to animals from the same cohort that experienced a chronic reduction in adult olfactory experience. We placed age-matched sets of full-sister honey bees, Apis mellifera, into two different olfactory conditions, in which animals were allowed to forage ad libitum. In one condition (T), we reduced the olfactory experience of foraging bees by placing them in a tent in which both sucrose and pollen resources were associated with a single odor. In the second condition (F), bees were allowed to forage freely and therefore receive a diversity of naturally occurring resource-associated olfactory experiences. We found that bees with a reduced olfactory experience had less developed antennal lobes when compared to experienced foragers, suggesting early-adult sensory experience influences the development of olfactory processing. We next measured the antennal lobe glomerular responses to odors using calcium imaging, and found that diverse olfactory experience of bees also enhances the inter-individual variation in the glomerular response profiles to odors. Last, we measured the impact of this treatment in an olfactory learning assay. We found that bees with a reduced olfactory experience had more difficulty picking an odor out of a mixture, which led them to generalize more (or respond similarly) to different mixture components than bees with richer olfactory experiences. Our study highlights the impact of individual experience at multiple levels (i.e., behavioral, physiological, developmental) on early olfactory processing.

Download Full-text

Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer’s Disease

Nutrients ◽

10.3390/nu10111765 ◽

2018 ◽

Vol 10 (11) ◽

pp. 1765 ◽

Cited By ~ 57

Author(s):

Vo Giau ◽

Si Wu ◽

Angelo Jamerlan ◽

Seong An ◽

SangYun Kim ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Bidirectional Communication ◽

The Central Nervous System ◽

Brain And Behavior ◽

Underlying Mechanisms ◽

And Behavior ◽

The Impact ◽

The Brain

The bidirectional communication between the central nervous system (CNS) and the gut microbiota plays a pivotal role in human health. Increasing numbers of studies suggest that the gut microbiota can influence the brain and behavior of patients. Various metabolites secreted by the gut microbiota can affect the cognitive ability of patients diagnosed with neurodegenerative diseases. Nearly one in every ten Korean senior citizens suffers from Alzheimer’s disease (AD), the most common form of dementia. This review highlights the impact of metabolites from the gut microbiota on communication pathways between the brain and gut, as well as the neuroinflammatory roles they may have in AD patients. The objectives of this review are as follows: (1) to examine the role of the intestinal microbiota in homeostatic communication between the gut microbiota and the brain, termed the microbiota–gut–brain (MGB) axis; (2) to determine the underlying mechanisms of signal dysfunction; and (3) to assess the impact of signal dysfunction induced by the microbiota on AD. This review will aid in understanding the microbiota of elderly people and the neuroinflammatory roles they may have in AD.

Download Full-text

Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration

International Journal of Molecular Sciences ◽

10.3390/ijms21207471 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7471 ◽

Cited By ~ 2

Author(s):

Francesco Gentile ◽

Pietro Emiliano Doneddu ◽

Nilo Riva ◽

Eduardo Nobile-Orazio ◽

Angelo Quattrini

Keyword(s):

Experimental Studies ◽

Population Based ◽

Strong Interactions ◽

Brain Physiology ◽

Parkinson’S Diseases ◽

Neurologic Disability ◽

The Central Nervous System ◽

And Behavior ◽

The Impact

Increasing evidence gives support for the idea that extra-neuronal factors may affect brain physiology and its predisposition to neurodegenerative diseases. Epidemiological and experimental studies show that nutrition and metabolic disorders such as obesity and type 2 diabetes increase the risk of Alzheimer’s and Parkinson’s diseases after midlife, while the relationship with amyotrophic lateral sclerosis is uncertain, but suggests a protective effect of features of metabolic syndrome. The microbiota has recently emerged as a novel factor engaging strong interactions with neurons and glia, deeply affecting their function and behavior in these diseases. In particular, recent evidence suggested that gut microbes are involved in the seeding of prion-like proteins and their spreading to the central nervous system. Here, we present a comprehensive review of the impact of metabolism, diet and microbiota in neurodegeneration, by affecting simultaneously several aspects of health regarding energy metabolism, immune system and neuronal function. Advancing technologies may allow researchers in the future to improve investigations in these fields, allowing the buildup of population-based preventive interventions and development of targeted therapeutics to halt progressive neurologic disability.

Download Full-text

Active Amyloid-β Vaccination Results in Epigenetic Changes in the Hippocampus of an Alzheimer’s Disease-Like Mouse Model

Current Alzheimer Research ◽

10.2174/1567205016666190827122009 ◽

2019 ◽

Vol 16 (9) ◽

pp. 861-870 ◽

Cited By ~ 1

Author(s):

Roy Lardenoije ◽

Daniël L.A. van den Hove ◽

Sophie E. Jung ◽

Monique Havermans ◽

Peter Blackburn ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Dna Methyltransferase ◽

Amyloid Β ◽

Active Immunization ◽

Active Immunotherapy ◽

Dna Hydroxymethylation ◽

Synaptic Markers ◽

The Impact

Background: While evidence accumulates for a role of epigenetic modifications in the pathophysiological cascade of Alzheimer’s disease (AD), amyloid-β (Aβ)-targeted active immunotherapy approaches are under investigation to prevent or slow the progression of AD. The impact of Aβ active vaccines on epigenetic markers has not been studied thus far. Objective: The current study aims to establish the relationship between active immunotherapy with a MER5101-based vaccine (consisting of Aβ1-15 copies conjugated with a 7 aa spacer to the diphtheria toxoid carrier protein, formulated in a Th2-biased adjuvant) and epigenetic DNA modifications in the hippocampus of APPswe/PS1dE9 mice. Methods: As we previously reported, immunotherapy started when the mice were 10 months of age and behavioral testing occurred at 14 months of age, after which the mice were sacrificed for further analysis of their brains. In this add-on study, global levels of DNA methylation and hydroxymethylation, and DNA methyltransferase 3A (DNMT3A) were determined using quantitative immunohistochemistry, and compared to our previously analyzed immunization-induced changes in AD-related neuropathology and cognition. Results: Active immunization did not affect global DNA methylation levels but instead, resulted in decreased DNA hydroxymethylation and DNMT3A levels. Independent of immunization, inverse correlations with behavioral performance were observed for levels of DNA methylation and hydroxymethylation, as well as DNMT3A, while Aβ pathology and synaptic markers did not correlate with DNA methylation levels but did positively correlate with DNA hydroxymethylation and levels of DNMT3A. Conclusion: Our results indicate that active Aβ vaccination has significant effects on the epigenome in the hippocampus of APPswe/PS1dE9 mice, and suggest that DNA methylation and hydroxymethylation may be involved in cognitive functioning.

Download Full-text