Epigenetics in Multiple Sclerosis: Molecular Mechanisms and Dietary Intervention

Author(s): Yamel Rito, Ivan Torre-Villalvazo, Jose Flores, Veronica Rivas, Teresa Corona*.

Journal Name: Central Nervous System Agents in Medicinal Chemistry

Volume 18 , Issue 1 , 2018

REVIEW ARTICLE

Epigenetics in Multiple Sclerosis: Molecular Mechanisms and Dietary Intervention

Yamel Rito1 , Ivan Torre-Villalvazo2 , José Flores1 , Verónica Rivas1 and Teresa Corona1, *

1Laboratory of Clinical Neurodegenerative Diseases, National Institute of Neurology and Neurosurgery of Mexico, Insurgentes Sur # 3877, CP 14269 Mexico City, México;
2Department of Physiology of Nutrition, Instituto Nacional de Ciencias Médicas y Nutrición. Av. Vasco de Quiróga #15, Tlálpan, CP 14080 México City, México

Abstract: Introduction: Multiple Sclerosis (MS) is a chronic, inflammatory, neurodegenerative demyelinating disease of the central nervous system (CNS). Unfortunately, MS causes important disability in young adults and its prevalence is increasing. While the etiology of MS etiology is not completely understood, it seems to be a multifactorial entity that is influenced by both genetic and epigenetic modifications. Epigenetic mechanisms add or remove different chemical groups for the activation or inhibition of gene expression to block the production of proinflammatory proteins. It is truly important to identify the factors that can trigger epigenetic changes in MS to complement the therapeutic approach, prevent disability and improve patients quality of life. Here, we have conducted a review of external factors that influence in MS and their epigenetic mechanisms. For example, hypomethylation can promote changes in the myelin and subsequent autoimmune reactions. Therapeutic tools can be used, including the histone deacetylase inhibitor Trichostatin A, which ameliorates demyelinating diseases in rodents. However, drugs are not only the therapeutic option: recent studies have also evaluated the therapeutic potential of several bioactive dietary components in neurodegeneration and axonal dysfunction. Numerous food-derived molecules exert important metabolic actions. These molecules include plant polyphenols such as catechins and isoflavones, Ω-3 and Ω-6 polyunsaturated fatty acids, short-chain fatty acids, sulfur-containing compounds such as dally sulfide and other compounds. Antioxidant and anti-inflammatory components in the diet involve transcription factors as well. However, many external factors have shown to influence MS, although no specific epigenetic mechanisms are known.

Conclusion: In this review, we gather both established and new evidences about the genetic, epigenetic and environmental factors influencing MS and the dietary components that could modulate MS relapse and progression.

Keywords: Axonal damage, bioactive dietary molecules, epigenetics, inflammation, multiple sclerosis, radical scavenging.


Article Information

Identifiers and Pagination:

Year: 2018
Volume: 18
Issue: 1
First Page: 8
Last Page: 15
Publisher Id: CNSAMC-18-1-8
DOI: 10.2174/1871524916666160226131842

Article History:

Received Date: July 30, 2015
Revised Date: February 19, 2016
Accepted Date: February 25, 2016

* Address correspondence to this author at the Laboratory of Clinical Neurodegenerative Diseases, National Institute of Neurology and Neurosurgery of México, Insurgentes Sur 3877, Colonia La Fama. Delegación Tlalpan, CP: 14269. México City, México; Tel: 56063822 Ext: 4004; E-mail: coronav@unam.mx

1. INTRODUCTION

1.1. MS and Prevalence

Multiple Sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system, with progressive neuroaxonal degeneration. It produces sensory, visual, motor and other important neurologic deficits in the patient. Additionally, MS is the most common cause of neurological disability in young adults. It has been recently estimated that there are approximately 2.3 million affected patients in the world [1, 2]. This disease is triggered by environmental factors in individuals with complex genetic risk profiles [3]. MS is more frequent in the outer latitudes including North America, Europe, Australia and Argentina [4, 5]. However, the frequency of MS is increasing in many other regions of Latin America [6, 7]. In Mexico, the prevalence of MS has been increased from 1.6 to 12 patients per 100,000 inhabitants in the last years [7, 8]. In Relapsing Remitting MS (RRMS), inflammation is transient and remyelination occurs but is mostly not durable. However, over time widespread microglial activation induces extensive and chronic neurodegeneration, and some cases are not treatable whit the currently available drugs [9]. These sharp increases in the MS prevalence highlight the necessity of novel therapeutic approaches to prevent and ameliorate the progression of the disease. However, the MS etiology is not completely understood, and thus, many researchers are working to elucidate the underlying molecular mechanisms involved in the development of this complex disease [10, 11]. In the last few years, novel and exiting mechanisms, such as epigenetic modifications of neuronal and glial DNA have been linked to neurodegeneration [12, 13]. In this review, we gather well-known and new evidences about the genetic, epigenetic and environmental factors influencing MS and the dietary components that could modulate MS relapse and progression.

1.2. Genetic Basis of MS

Genetic mutations are irreversible alterations in the DNA sequence that involve a base exchange or inversion or deletion of a fragment of DNA, leading to a loss or alteration of genetic information [14, 15]. Alterations in the DNA integrity of the gametes can lead to genetic diseases in the newborn. Genetics plays a significant role in MS, as seen by the fact that most of the patients have the genetic expression of HLA-DR2 (DRB1*1501, DQB1*0602) on chromosome 6p21, which encodes for glycoproteins on the cell surface for antigen recognition [15]. However, their concordance for homozygous twins is just 20-30%. The HLA DR2 haplotype confers a relative risk of 3 in heterozygosity and 6 in homozygosity [16]. Taken together, these findings suggest that the presence of a specific HLA allele is not enough to develop MS [17]. Another situation that supports the multifactorial influence of MS is the variability between MS and HLA genes among populations. A significant association of DRB1*0403 and DRB1*0802 with MS was shown in a Mexican population [18]. In contrast, the Lacandonians, an ethnic Mexican group did not develop MS disease [19].

1.3. Epigenetic Mechanisms and MS

Epigenetic modifications are the set of reversible mechanisms necessary to modify the phenotype of a cell in response to environmental or endocrine factors [20 - 24]. Epigenetic mechanisms consist of the addition or removal of different chemicals groups (methyl, acetyl, phospho, ribosyl and ubiquitin) either directly on the DNA molecule or indirectly on its associated histones. These modifications are mediated by the action of several enzymes that activate or inhibit gene expression [23, 25]. The discovery of the epigenetic regulation of the structure and function of chromatin revealed that gene expression is not just a predetermined and strict process governing the biological functions of the body, it is also influenced and modified by physical or environmental factors in order to achieve the necessary adaptations to survive in a dynamic environment. Unfortunately, epigenetic modifications of the DNA or the histone code can also produce diseases.

1.3.1. DNA Methylation

DNA methylation is one of the most important and well studied epigenetic processes, even in autoimmune diseases [24, 26]. The methyl group (-CH3), can be added to cytosine residues near the CpG sequence and, produces genes silencing and blocking their targets of action. One of the enzymes that carries out DNA methylation is the DNA methyltransferases (DNMTs) [25]. Some investigations have shown different patterns of DNA methylation in the brains of patients with MS. One interesting finding was that there was 33% less methylation in the white matter brain of MS patients than in controls [20, 27]. This finding suggests that some genes are not express in MS patients. Additionally, hypomethylation was found at the promoter region of PADl2 (peptidyl arginine deiminase, type II), which catalyzes the citrullination of myelin basic protein (MBP). The result of PAD12 hypomethylation in MS is the inhibition of the MBP production, promoting changes in the myelin ultrastructure and its dysfunction [28]. Immunological cells such as lymphocytes naïve CD4+ T cells express DNA methylation changes during their differentiation into Th1 or Th2 cells. The reduction of methylation in these cells is related to autoimmune reactions, one of the most accepted action mechanisms of action in MS. Interleukin 17A (IL) is one of the most important inflammatory participants in MS. The hypomethylation of the IL-17A promoter increases the T cell differentiation into TH17 cells, promoting IL-17 production and CNS inflammation. In contrast, the deficiency of CD44 on CD4+T inhibits Th1/Th17 cells differentiation, conferring protection in experimental autoimmune encephalomyelitis (EAE) [24, 29]. Interestingly, CD44-deficiency led to increased hypermethylation of the ifnγ/il17a gene and marked demethylation of the il4/ foxp3gene promoter [29].

1.3.2. Histone Acetylation

Histones are positively-charged proteins that bind to negatively-charged DNA molecules. Histones wrap the threads of DNA like reels, forming structures called nucleosomes. The N-terminal region of histones or so called “tails” are important for chromatin compaction and gene regulation [25]. The acetylation of the lysine residues in the histone tails is catalyzed by the histone acetyltransferases (HATs), enhancing the transcriptional activity, whereas deacetylation is catalyzed by the histone deacetylases (HDACs) and is associated with gene repression [22, 30]. Oligodendrocytes are specialized glial cells responsible for myelin production. It has been demonstrated that there is a marked deacetylation in oligodendrocyte histones in MS patients. This deacetylation is more frequent in chronic MS lesions than in early MS lesions [31]. In addition, the histone deacetylase-inhibitor Trichostatin A, can ameliorate disease progression in experimental autoimmune encephalomyelitis (EAE) animal models [32]. Additinally, genetic variability in the HDAC genes influences the brain volume of MS patients. Furthermore, the expression of IL-33 regulates genes to HDAC activity, and is increased in patients with RRMS. [33]. Taken together, these data suggest that histone deacetylation is a defense against demyelination.

1.4. Micro RNA (miRNA) –Mediated Gene Silencing

In addition to epigenetics, another mechanism of transcriptional regulation, micro RNA (miRNA)-mediated gene silencing, has recently been described. miRNAs are small RNA molecules, consisting of 21 to 23 nucleotides that are synthesized after a cleaving processes in the nucleus. Once the miRNA is in the cytoplasm, it forms an RNA-induced silencing complex (RISC) for the delivery of the miRNAs to the mRNAs to be silenced. It has been observed that interaction between different types of miRNA and mRNAs can modulate cellular development, differentiation, proliferation and/or apoptosis [25]. The miRNAs that that have been most studied in MS patients are: hsa-miR-326, hsa-miR-155, hsa-miR- 146a, and hsa-miR-142-3p which are overexpressed in patients with MS [34]. The miR155, miR34a and miR326 were all highly upregulated in active MS lesions. This is likely due to the influence of miRNAs on the reduction of CD47 expression, which inhibits the phagocytic activity of macrophages (Table 1). Additionally, the up regulation of miR18b and miR599 expression is associated with MS relapse, while the overexpression of miR96 is associated with MS remission [35]. The differentiation of T-helper 17 (TH17) cells, is influenced by miR155 and miR326 expression. The miR326 targets are the transcription factors Cets1 or p54, which inhibits the differentiation of naive T cells into the TH17 phenotype [35]. Otherwise, the expression of miR155 is involved in inflammatory processes, that are dependent on Toll-like receptors [36]. Therefore, mice without miR155 are highly resistant to the development of EAE [37]. miR17 and miR20a inhibit T cell activation and, are down regulated in all forms of MS [38].

Table 1. Epigenetic mechanism in MS.

Mechanism Action Effects
Methylation Add methyl group to cytosine= genes silencing. MS patients have hipomethylation.
PAD12 hipomethylated inhibit MBP production and contributes to demyelination.
Th1 and T2 DNA´s hypomethylation produce autoinmmune reactions.
Hypomethylation of IL-17A increases the T cell differentiation.
Deacetylation of Histones Catalyzed by HDACs = genes repression. Deacetylation in histone´s oligodendrocytes generates demyelination.
Deacetylases´s inhibitor Trichostatin A, ameliorated the disease in EAE.
Micro RNA (miRNAs) Expression o inhibition of miRNAs produce develop, differentiation,
proliferation and/or apoptosis of the cells.
↑ regulation of miR¬18b and miR¬599 = relapses in MS.
↓ regulation of miR¬96 = remission.
No expression of miR¬155 = resistant to development of EAE.

PADl2: peptidyl arginine deiminase, type II, HDACs: histone deacetylases. MBP: Myelin Basic Proteína. EAE: Experimental Autoimmune Encephalomyelitis.

These main mechanisms show us the important influence of epigenetics in MS. Therefore, it is of critical importance to identify the associated external factors and their links to the epigenetic actions in MS. Next, we summarize the multiple known contidions and factors required for the development of MS. However, not all of them have been shown to have molecular mechanism (Table 2).

1.5. External Factors Involved in MS

1.5.1. Virus

Epstein Barr Virus (EBV is the infectious agent most frequently related to MS. Several studies have demonstrated the presence of a higher risk of developing MS in individuals previously infected with mononucleosis [39, 40], and a meta-analysis also supported this association [41]. Circular EBV genomes may increasing methylation which promotes the activity of B lymphocytes [42]. Another agent associated with MS is the Varicella Zoster Virus (VZV) [43] which confers a risk of threefold developing MS [44]. VZV´s DNA was also found in the cerebrospinal fluid (CSF) of 65% of studied cases with progressive MS [45]. In Mexico, VZV was the most frequent virus to be identified in relapses of MS patients [46].

1.5.2. UV Radiation

It is known that the high prevalence and incidence of MS increase in extreme latitudes, suggesting an environmental factor. Interestingly, individuals who move to areas with a high MS prevalence before 15 years of age have an increased risk of developing disease. This phenomenon has been attributed to UV light exposure [47]. Some factors could explain this, such as vitamin D serum levels, which depend on the amount of sun exposure. However, the correlation between UV light exposure and MS risk is not consistent across all regions studied, as this correlation was not observed in all tropical countries [48].

1.5.3. Vitamin D

The active form of vitamin D, 1,25-hydroxyvitamin D3, is a steroid hormone produced in the skin following exposure to sunlight. Vitamin D has been related to immunoregulation in MS [49], and the vitamin D receptor has a retinoid action in the cell´s nucleus that influences the overall genomic expression [50, 51]. Low vitamin D levels are associated with a higher risk of developing MS [52, 53]. However, some studies did not find differences between vitamin D levels of MS patients and controls in African-American and Hispanic populations [52, 54 - 56]. This finding suggests that low concentrations of vitamin D do not confer the same risk to all races or ethnicities. One study showed that the vitamin D receptor suppresses the transcription of IL-17, an important proinflammatory factor in MS, through the histone deacetylase [50].

1.6. Dietary Factors

We believe that dietary factors deserve special attention because they have a major role in metabolism and are a necessary and daily resource that can be modified. The energy density of the diet and its macronutrient composition determines the amount of substrates available for catabolic and anabolic pathways in the different organs. However, there are numerous food-derived molecules that exert important metabolic actions, whose mechanisms are not yet well defined. This is therefore a fertile area for future research [57]. These molecules include plant polyphenols such as catechins and isoflavones, Ω-3 and Ω-6 polyunsaturated fatty acids (PUFAs), short-chain fatty acids, sulfur-containing compounds such as diallyl sulfide and other compounds [57]. The therapeutic potential of these molecules has been evaluated in several basic and clinical studies, which have revealed important beneficial effects of these factors in disease progression [58 - 61]. Recent studies have evaluated the therapeutic potential of bioactive dietary components on neurodegeneration and axonal dysfunction in (EAE) and in patients with MS. Otherwise, the dietary intake of polyphenols is known to attenuate oxidative stress and reduce the risk for related neurodegenerative diseases such as MS [62]. The protective effects of dietary compounds against neuronal damage can be divided into two broad categories: radical scavenging and anti-inflammatory actions. These actions are exerted by genomic, non-genomic and epigenetic mechanisms (Fig. 1).

Many of the beneficial actions of bioactive vegetable compounds involve the modulation of specific transcription factors (TFs). TFs are proteins that bind to response elements located in the promoter/enhancer region of a gene and regulate gene expression. Thus, the activity of TFs is involved in all cellular functions, including substrates flux, cellular growth and inflammatory responses. Some TFs possess a ligand-binding domain to which specific molecules bind to it, activate their function. These TFs are called nuclear receptors and are the molecular effectors of steroid hormone action, such as estrogens and corticoids (e.g. vitamin D). Interestingly, in recent years several nutrient-activated TFs have been characterized. These nuclear receptors directly bind nutrients or their derivatives in a similar way to how hormones bind their respective receptors, adding a new layer to metabolic regulation [63].

The Peroxisome Proliferators-Activated Receptor (PPAR) family of nuclear receptors comprise a group of ligand-activated TFs that can bind several endogenous and diet-derived molecules such as fatty acids and their derivatives, flavonoids and stilbenes [64]. It has been demostrated that the activation of PPARγ exerts anti-inflammatory and neuroprotective effects and that PPARγ agonists are thus potential therapeutic agents in brain diseases including MS. Arctigenin is a molecule extracted from Arctium lappa that binds and activates PPARγ [65]. A recent study demonstrated that arctigenin reduces inflammation and demyelination in mice with EAE possibly via PPARγ activation [66]. The turmeric derivative curcumin has also a neuroprotective activity [67].

The transcriptional activities of PPARγ are potentiated by the chromatin-remodeling activities of the PPARγ coactivator 1-α (PGC1α). PGC1α activation in the brain induces mitochondrial biogenesis and enhances antioxidant defenses, reducing ROS production and axonal damage [68]. Several studies have shown that dietary components, such as resveratrol can enhance PGC1α activity in neurons and glial cells, exerting protective effects in the brain [69]. The PPARγ-PGC1α molecular complex, is finely modulated by the activity of the transcriptional modulators called sirtuins. Sirtuins are members of the HDAC class III family of proteins, which mediated couples lysine deacetylation reaction to NAD hydrolysis [70]. SIRT1 is the first sirtuin described and is one of the most studied at the molecular and physiological levels. SIRT1 plays a key role in the cellular responses to nutritional and environmental perturbations, such as fasting, DNA damage, and oxidative stress by triggering nuclear transcriptional programs that up regulate mitochondrial biogenesis, metabolism and antioxidant capacity [71]. It is interesting that resveratrol and dietary NAD+ precursors, such as nicotinic acid, nicotinamide, and nicotinamide riboside increase SIRT1 activity.

Fig. (1). Molecular mechanisms involved in neuronal injury during MS and the potential therapeutic activities of dietary bioactive molecules. Different molecules found in fish and vegetables exert beneficial effects in axonal damage and neurodegeneration by mechanisms involving modulation of the transcription factor PPARγ and the coactivators PGC1α and SIRT1. These molecules can also inhibit HDAC activity, modulating neuronal epigenetic remodeling. In neurons, PPARγ-PGC1α-SIRT1 activation increases mitochondrial function and antioxidant capacity, reducing the accumulation of free radicals. PPARγ-PGC1α-SIRT1 can be also activated in microglia, lymphocytes and macrophages, reducing the synthesis and release of pro-inflammatory cytokines. All these combined effects could prevent or ameliorate axonal damage and neurodegeneration during MS.
Table 2. Environmental factors involved in MS.

Factor Mechanism of Action References
Gender: most in females. Not well established
Estrogens act in intracellular receptors, and regulate genes.
Kucukali,C. [22]
Greer, JM [75]
Voskuhl R.R. 76]
Virus: Epstein Barr Virus (EBV), Varicella zoster virus (VZV). Circular EBV genomes increasing methylation producing cell B activity. Niller [42]
UV radiation Associated to vitamin D production. Taylor B.V [47]
Vitamin D
Related with immunoregulation.
Vitamin D receptor has a retinoid action in the cell´s nucleus, reaching an influence over genome.
Transcription of IL-17, though to the histone deacetylase
Joshi, S. [77]
Diet
Polyphenols: catechins and isoflavones. Attenuate oxidative stress and reduce the risk for related neurodegenerative. Joven, J. [57]
Arctigenin. Reduces inflammation and demyelination, because activates PPARγ. Li. W [66]
Turmeric derivative curcumin Activates PPARγ Liu. Z [67]
Resveratrol Enhance PGC1α activity in neurons and glial. [76]
Sulforaphane compounds
(Broccoli)
Intestinal microbiota.
S-allylmercaptocysteine from the garlic.
Inhibition of HDAC activity increases global histone H3 and H4 acetylation modulating the expression of several genes Myzak M.C [73]
Nian, H [74]
Others factors
Smoking Increase the risk for MS
Accelerated the conversion to SPMS.
Healy, Riise, Hernan, Pittas, Di Pauli [78 - 82]
Metals: mercury, silver, and gold Induce autoimmunity. Silver and gold could generate antinuclear antibodies, against the nucleolar proteins.
Mercury induces necrosis.
Martinez-Zamudio R [83]
Organic solvents: paint thinner,
nail polish removers, glue solvents, etc
A meta-analyses disclosed significant association between heavy metals and MS Barragan-Martinez. Landtblom [84, 85]

PPARγ: peroxisome proliferators-activated receptor γ; HDAC: histone deacetylase (HDAC); SPMS: secondary progressive multiple sclerosis.

Some dietary compounds can also act as weak ligands for HDAC, inhibiting their activity. The inhibition of HDAC activity increases global histone H3 and H4 acetylation by modulating the expression of several genes [72]. Cruciferous vegetables such as broccoli are rich in sulforaphane compounds and it has been reported that a single dose of 68g (one cup) of broccoli sprouts influences the HDAC activity in circulating humans cells, with a level of HDAC inhibition and histone hyper acetylation similar to that achieved with clinically utilized HDAC inhibitors [73]. Butyrate derived from the fermentation of dietary fiber by the intestinal microbiota and s-allylmercaptocysteine derived from metabolism of garlic dially l sulfides have also HDAC inhibitory activities [74]. It has been proposed that the rapid and transient epigenetic changes induced by dietary molecules actually have biological significance. Histone remodeling induced by weak HDAC ligands might prime normal cells to respond effectively to exogenous insults (e.g., toxins and oxidative stress, among others), thereby safeguarding cells against the progression of epigenetic-related diseases such as cancer, cardiovascular diseases and neurodegeneration [72].

CONCLUSION

External factors including hormones, VEB, vitamin D, and dietary bioactive molecules (catechins, isoflavones, arctigenin, etc.) can trigger epigenetic mechanisms such as methylation and deacetylation, which can generate important genetic changes and protective effects in MS patients. Increasing our knowledge about the molecular mechanisms involved in MS is thus critical for the development of improved therapeutic approaches. Diet is a potentially modifiable factor because dietary bioactive molecules exert beneficial effects on critical transcriptions factors involved in axonal injury and neurodegeneration. Thus, careful dietary recommendations could improve the quality of life of MS patients while paving the way for the development of new therapeutic interventions.

LIST OF ABBREVIATIONS

DNMTs = DNA Methyltransferases
EAE = Experimental Autoimmune Encephalomyelitis
HATs = Histone Acetyltransferases
HDAC = Histone Deacetylase
MBP = Myelin Basic Protein
miRNAs = Micro RNA
MS = Multiple Sclerosis
NRF2 = Erythroid-2 Related Factor
PAD12 = Peptidyl Arginine Deiminase, Type II
PPARγ = Peroxisome Proliferators-Activated Receptor γ
RISC = RNA-induced Silencing Complex
SIRT1 = Sirtuin 1
TH17 = T-helper 17

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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