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The epigenetics of multiple sclerosis and other related disorders

Multiple Sclerosis and Related Disorders, 2, 3, pages 163 - 175

Abstract

Multiple Sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system (CNS) gray and white matter. Although the cause of MS is unknown, it is widely appreciated that innate and adaptive immune processes contribute to its pathogenesis. These include microglia/macrophage activation, pro-inflammatory T-cell (Th1) responses and humoral responses. Additionally, there is evidence indicating that MS has a neurodegenerative component since neuronal and axonal loss occurs even in the absence of overt inflammation. These aspects also form the rationale for clinical management of the disease. However, the currently available therapies to control the disease are only partially effective at best indicating that more effective therapeutic solutions are urgently needed.

It is appreciated that in the immune-driven and neurodegenerative processes MS-specific deregulation of gene expressions and resulting protein dysfunction are thought to play a central role. These deviations in gene expression patterns contribute to the inflammatory response in the CNS, and to neuronal or axonal loss. Epigenetic mechanisms control transcription of most, if not all genes, in nucleated cells including cells of the CNS and in haematopoietic cells. MS-specific alterations in epigenetic regulation of gene expression may therefore lie at the heart of the deregulation of gene expression in MS. As such, epigenetic mechanisms most likely play an important role in disease pathogenesis.

In this review we discuss a role for MS-specific deregulation of epigenetic features that control gene expression in the CNS and in the periphery. Furthermore, we discuss the application of small molecule inhibitors that target the epigenetic machinery to ameliorate disease in experimental animal models, indicating that such approaches may be applicable to MS patients.

Highlights

 

  • Review update on the role of epigenetics in multiple sclerosis and other related disorders.
  • Review update on the application of epigenetic drugs in animal models.
  • Valproic acid reduces neurological disease in EAE in Biozzi ABH.

Keywords: Epigenetics, Multiple sclerosis, DNA methylation, Histone modifications, Animal models, Epigenetic drugs.

1. Introduction

MS is a chronic inflammatory demyelinating and neurodegenerative disease of the CNS, the cause of which remains elusive. An estimated 2.5 million people in the world have MS, although there is a distinct distribution with the disease being more common in northern and southern latitudes. The disease onset is mostly in young adults with a prevalence for women.

Genetic linkage studies and genome-wide meta-analyses have identified genes that may confer susceptible individuals to develop disease (Sawcer et al, 2011 and Patsopoulos et al, 2011). Many of these genes play a role in the immune system with a prominent role for major histocompatibility complex (MHC) class II molecules in particular defined HLA-DRB1 alleles ( Sawcer et al., 2011 ). However, if the information contained within the DNA would solely determine disease susceptibility, the concordance rate to develop MS in monozygotic twins should be the same. However, there is a low concordance rate for MS in monozygotic twins (26%) ( Ebers et al., 1986 ) indicating that genetic factors alone do not contribute to disease. This suggests that epigenetic changes may also influence MS susceptibility ( Koch et al., 2013a ). It is widely appreciated that environmental factors play an important role in the establishment of the epigenome (Cobiac, 2007, Foley et al, 2009, and Jaenisch and Bird, 2003). Since epigenetic alterations accumulate in time, environmental factors consequently have profound effects on the cellular repertoire of expressed genes ( Fraga et al., 2005 ) and may provide an explanation for the impact of the environment to disease pathogenesis.

The influence of environmental factors on disease susceptibility is illustrated by several studies, which have shown that when migration occurs before the age of fifteen, the migrant acquires the new region's susceptibility to MS. When migration occurs after the age of fifteen, the migrant retains the susceptibility of the home country ( Kurtzke, 2000 ). One of the factors thought to contribute to these manifestations is sunlight exposure reported to have a protective role in MS development, possibly mediated by vitamin D ( Kragt et al., 2009 ). This may explain the geographical prevalence of MS world-wide, due to reduced sunlight exposure in the further northern and southern latitudes. One of the mechanisms by which vitamin D could act is through modulation of the immune response at multiple points by binding to the vitamin D receptor, which is expressed on monocytes, dendritic cells and activated T cells ( Smolders et al., 2008 ). It has been demonstrated in vitro that vitamin D modulates the maturation and differentiation of dendritic cells and therefore could promote a more tolerogenic state of the immune system by the production of IL-10 ( Smolders et al., 2008 ). Further support of a beneficial effect of vitamin D comes from experimental studies in the autoimmune model of MS experimental autoimmune encephalomyelitis (EAE) in which vitamin D has a beneficial effect on onset and severity of the disease ( Niino et al., 2008 ). In addition, the role of environmental factors cooperating with the genetic background to determine the risk for MS has been recently clarified ( Handel et al., 2010 ). For example, sunlight-induced vitamin D, and its effects on epigenetic regulation of MHC gene expression is likely to co-define the MS risk. Additional environmental factors that possible contribute to this latitude-dependent susceptibility to develop MS are smoking, infections or diet ( Koch et al., 2013a ). In particular Epstein-Barr Virus (EBV) is associated with MS since all patients have the virus ( Pakpoor et al., 2013 ). However, whether the strong epidemiological association between MS and EBV infection is a consequence rather than a cause of the disease remains to be firmly established ( Pakpoor et al., 2013 ). Interestingly, EBV utilizes DNA methylation to avoid immune recognition ( Tao and Robertson, 2003 ). It is thus tempting to speculate that EBV components could also influence the well-orchestrated epigenetic cellular programs. Therefore, epigenetic mechanisms influenced by the environment may play an important role in the onset and progression of the disease in susceptible individuals.

2. Epigenetics

Epigenetics is one of the most promising and rapidly expanding fields in biomedical research. It refers to the study of mitotically and/or meiotically heritable changes in gene expression that occur without a change in the DNA sequence ( Berger et al., 2009 ). Epigenetic mechanisms control gene expression by determining the accessibility of the transcriptional machinery to regulatory regions of genes. Since all nucleated cells contain the same genetic material, epigenetic mechanisms determine the function of cells in a specific manner by controlling its gene expression profile. As such, epigenetic mechanisms play an essential and fundamental role in the transcriptional control of genes, maintenance of cellular identity, cell activation, cellular repair and stress processes. It can therefore be envisioned that disturbances in epigenetic processes lead to oncogenic transformation of cells as well as monogenic or complex diseases. Moreover, these epigenetically controlled gene expression patterns can be passed to daughter cells upon cell division or even transgenerationally ( Guerrero-Bosagna and Skinner, 2012 ). This latter effect is illustrated by several studies, which show the transgenerational effect of maternal and paternal environmental exposures on the offspring of next generation(s) (Bygren et al, 2001, Kaati et al, 2002, and Pembrey et al, 2006).

In its natural state DNA in the nucleus is packaged into chromatin, a highly organized and dynamic protein-DNA complex, which consists of DNA, histones and non-histone proteins (Luger et al, 1997 and Kouzarides, 2007). The fundamental subunit of chromatin is the nucleosome which is composed of an octamer of four core histones: two each of H2A, H2B, H3 and H4, surrounded by 147 base pairs of DNA (Luger et al, 1997 and Kouzarides, 2007) ( Figure 1 ). Epigenetic mechanisms alter the structure of chromatin by modification of DNA and by modification or rearrangement of nucleosomes, which include post-translational modifications of histones ( Jenuwein and Allis, 2001 ). Accessible or relaxed chromatin (euchromatin) allows transcription factors to interact with their cognate binding sites within regulatory regions of genes, such as proximal promoters and enhancer/silencers, while inaccessible or compressed chromatin (heterochromatin) does not permit these protein/DNA interactions. Of note is that these epigenetic modifications are reversible allowing the chromatin structure to switch between open and closed states. In this way, global gene activation and local control of gene-specific transcription is exerted by components of the epigenetic machinery. Importantly, epigenetic processes are not static, but dynamic, changing e.g. during differentiation and in response to environmental factors (Alkemade et al, 2010, Fraga et al, 2005, and Kaminsky et al, 2009).

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Fig. 1 Schematic representation of chromatin. Euchromatin is recognized by low levels of DNA methylation (open white circles), and high levels of acetylated histones (light green triangles) and histone methylation modifications correlated with activation (dark green circles). These histone modifications are recognized by code-readers associated with open chromatin (alternatively shaped figures). Heterochromatin is hallmarked by high density of DNA methylation (black circles) and high levels of repressive histone methylation modifications (closed red circles). These histone modifications are recognized by code-readers associated with repressed chromatin (alternatively shaped figures). KATs are responsible for acetylation of histone tails whereas HDACs remove these acetylation modifications associated with active chromatin. Methylation of histone tails is catalyzed by KMTs whereas KDMs remove these modifications. DNA methylation is catalyzed by DNMTs. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

2.1. DNA methylation

DNA methylation is the best-studied epigenetic modification that involves the addition of a methyl group to the C5 position of cytosine residues in a CpG dinucleotide context, converting cytosine residues into 5-methylcytosines. This reaction is exerted by DNA methyltransferases (DNMTs) and S-adenosylmethionine as a methyl group donor. Of the DNMTs, DNMT3A and DNMT3B are responsible forde novomethylation; whereas the maintenance DNA methyltransferase, DNMT1, ensures that the epigenetically modified cytosine residues are maintained after cell division. The reversible nature of this modification is underscored by the finding that DNMTs are also involved in removing the methyl group from 5-methylcytosines (Kangaspeska et al, 2008, Metivier et al, 2008, and Kim et al, 2009). In addition, the Ten-Eleven Translocation (TET) family of enzymes have the capacity to convert 5-methylcytosine into 5-hydroxymethylcytosine ( Williams et al., 2012 ). This conversion could be followed by passive or active demethylation restoring the unmethylated state of CpG islands.

CpG residues are underrepresented in the human genome but are highly enriched in so-called CpG islands in most gene promoters ( Takai and Jones, 2002 ). In general, gene expression is associated with unmethylated CpGs in gene promoters, while CpG methylation is associated with transcriptional repression ( Kulis and Esteller, 2010 ) ( Figure 1 ). More recently, the involvement of so-called CpG island shores, at more distal locations from gene promoters in gene transcription, has become apparent ( Irizarry et al., 2009 ). In addition, the crucial role that diet plays in epigenetic processes is shown by the requirement of co-factors folate and vitamins B12 and B6 by enzymes involved in the DNA methylation cycle ( Fuso, 2013 ).

2.2. Post-translational histone modifications

Post-translational modifications of histone proteins are also key-components in the epigenetic regulation of genes. Histones are subject to many modifications mostly in the N-terminal tails (Bernstein et al, 2007, Brunner et al, 2012, and Wang et al, 2007). Modifications of histone tails involved in gene transcription include acetylation and methylation of lysine residues. Whereas acetylation of lysine residues in histone tails is correlated with gene activation ( Struhl, 1998 ), the influence of histone methylation on gene transcription depends on the exact lysine residue methylated and the number of added methyl groups: mono-, di- or trimethyl ( Kouzarides, 2007 ). For instance, tri-methylation of histone H3 at lysine 9 (3MeK9H3) and at lysine 27 (3MeK27H3), and of histone H4 at lysine 20 (3MeK20H4) are marks of gene repression (Cao and Zhang, 2004, Li et al, 2007, Martin and Zhang, 2005, Rice et al, 2003, and Schotta et al, 2004). Counteracting these repressive modifications are the transcriptionally permissive modifications tri-methylation of histone H3 at lysine 4 (3MeK4H3) and at lysines 36 and 79 (Li et al, 2007, Martin and Zhang, 2005, Wang et al, 2009, and Yan and Boyd, 2006). Together these modifications form a ‘histone code,’ like the genetic code, that controls transcription levels of genes ( Strahl and Allis, 2000 ).

2.2.1. Enzymes that modify histones by acetylation and methylation

Enzymes that chemically modify histones by adding or removing specific acetylation or methylation modifications on lysine residues of core histones have been, and continue to be identified. Histone acetylation depends on the activities of lysine acetyltransferases (KATs), and histone deacetylases (HDACs) and SIRTUINS (SIRTS). HDACs may be classified into four subfamilies (class-I, -IIa/IIb, -III and -IV), which possess in general non-overlapping functions and each having a unique expression pattern ( Kortenhorst et al., 2006 ) ( Table 1 ). Likewise, histone methylation relies on the activities of lysine methyltransferases (KMTs) and lysine demethylases (KDMs). In this way the enzymes promote a return to respectively repressive or active chromatin structure ( Bannister and Kouzarides, 2011 ). Of note is that the enzymes that modify histones act in concert with DNA methyltransferases (Vaissiere et al, 2008 and Vire et al, 2006). In this way, these enzymes control global gene activation and local control of gene-specific transcription, and establish the cellular portrait of expressed genes. Besides their important role in the modification of histones, these enzymes also modify and thereby influence the activities of non-histone targets involved in many cellular processes including in axonal degeneration (Egorova et al, 2010 and Yao and Yang, 2011).

Table 1 Families of histone deacetylases.

Class  
I HDAC: 1,2,3,8
IIa HDAC: 4,5,7,9
IIb HDAC: 6,10
III HDAC: SIRT1-7
IV HDAC: 11
2.2.2. Additional histone modifications

While lysine methylation and acetylation are the most studied modifications, there are many more histone modifications known. Arginine residues can also be methylated and acetylated. In the case of methylation, repression or activation of transcription depends on which arginine residue is methylated and the type of methylation i.e. mono- or di-(asymmetric or symmetric) ( Bannister and Kouzarides, 2011 ). Sumoylation and ubiquitination of lysine residues have also been observed ( Wang et al., 2007 ). Sumoylation appears to be associated with transcriptional repression ( Garcia-Dominguez and Reyes, 2009 ), whereas ubiquitination has been suggested to play a role in transcriptional activation and elongation ( Shukla et al., 2009 ). Other post-translational histone modifications that have been described include phosphorylation of serine and threonine residues, ADP-ribosylation of glutamic acid and arginine, deimination of arginine residues which are converted to citrulline and proline isomerisation ( Bannister and Kouzarides, 2011 ).

2.3. Histone code readers

The ‘histone code’ can be read by so-called code-readers, chromatin-associated factors that specifically interact with modified histones ( Bannister and Kouzarides, 2011 ). For instance Heterochromatin Protein 1 (HP1) recognizes and binds to the 3MeK9H3 mark, while Polycomb Group Proteins interact with the 3MeK27H3 mark for maintenance of repressive chromatin states. The 3MeK4H3 mark is bound by an ATP-dependent remodeling enzyme chromodomain helicase DNA binding protein 1 (CHD1), which is capable of repositioning nucleosomes facilitating transcription ( Bannister and Kouzarides, 2011 ).

Methylated CpG dinucleotides are bound by methyl CpG binding protein 2 (MeCP2) which can also be regarded as a code-reader. MeCP2 subsequently acts as a platform for recruitment of HDACs and transcriptional repressors, and of HMTs (Bird, 2002 and Fuks et al, 2003). This leads to deacetylation and methylation of histones associated with CpG methylated DNA, which ultimately results in a stable transcriptionally repressive chromatin environment and gene silencing.

2.4. miRNA-associated epigenetic regulation

MicroRNAs (miRNA) are a class of endogenous small non-coding RNAs that consist of about 22 nucleotides and play critical roles in various cellular processes including in differentiation. miRNAs can act in several ways in epigenetic regulation by post-transcriptional silencing through target mRNA degradation or by translational inhibition of mRNAs encoding DNMTs, histone modifying activities or code readers ( Sato et al., 2011 ) ( Figure 2 ). Notably, transcription of the genes encoding miRNAs themselves is regulated by epigenetic processes such as DNA methylation ( Kulis and Esteller, 2010 ). Several miRNAs appear to play a role in oligodendrocyte differentiation, and in immune system development and regulation (Li and Yao, 2012 and Thamilarasan et al, 2012).

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Figure 2 Schematic representation of translational repression and mRNA degradation by miRNAs. A miRNA gene is transcribed to yield pre-miRNA, which is cleaved by Drosha and transported out of the nucleus. Pre-miRNA is then cleaved by Dicer to form a short double stranded mature miRNA. The double stranded miRNA separated into two single strands and complexes with Risc. The miRNA/Risc complex binds to its target mRNA, which is translationally repressed or degraded.

Due to the reversible nature of epigenetic histone modifications, the chromatin-modifying enzymes are interesting therapeutic targets (Adcock, 2006 and Cole, 2008). A myriad of small molecule inhibitors that can influence the enzymatic activity of these chromatin-modifying enzymes are currently being tested for their efficacy in a variety of pathologies including neurological disorders ( Mai, 2007 ). Some of these issues, summarized in Table 2 are discussed below.

Table 2 Epigenetic therapies in experimental models of CNS autoimmune and neurodegenerative diseases.

Drug Action Model Mechanism Reference
VPA HDAC class I and IIa, inhibitor EAE in rats Inhibits neurological disease. Decreased macrophage and T cell infiltration. Th1, Th17 switch to Th2 and T reg. Zhang et al. (2012)
AD mouse Inhibits Abeta production. Reduces neuronal loss, plaque formation and behavioral deficits Long et al. (2012)
Qing et al. (2008)
HD mouse model Alleviated locomotor deficits, depressive- and anxiety-like behaviors. Improved motor skill, learning and coordination. Chiu et al. (2011)
 
Vorinostat (SAHA) HDAC class I, IIa, IIb and IV inhibitor EAE Inhibition of Th1 and Th17 responses Ge et al. (2013)
AD mouse Restored contextual memory Kilgore et al. (2010)
R6/2 HD mouse Improved the motor impairment Hockly et al. (2003)
 
MS-275 (Entinostat) HDAC-1 and HDAC-3 inhibitor EAN Attenuates accumulation of macrophages, T cells and B cells, and demyelination. Reduces pro-inflammatory cytokines. Increases Foxp3+ cells and M2 macrophages Zhang et al. (2010)
AD cerebral amyloidosis Ameliorates inflammation and cerebral amyloidosis Zhang and Schluesener (2013)
 
D-β-hydroxy butyrate HDAC class I and IIa inhibitor transgenic R6/2 mice HD Extends life span and attenuates motor deficits Lim et al. (2011)
 
TSA HDAC class I, IIa, IIb and IV inhibitor EAE Reduces spinal cord inflammation, demyelination, neuronal and axonal loss and decreases neurological disease Camelo et al. (2005)
 
Resveratrol Sirt 1 activator (HDAC class III) EAE Reduced optic neuritis attenuates neuronal damage. Reduces clinical disease Shindler et al. (2010)
6-OHDA-PD rat model Neuroprotective effect due to decreased the levels of COX-2 and TNFα mRNA in the substantia nigra Jin et al. (2008)
 
Curcumin KAT inhibitor EAE Decreased inflammation and IL-17, TGFβ, IL-6, IL-21 STAT3, RORγ Xie et al. (2009)
AD model Interferes with plaque formation Lim et al. (2001)
MTPT PD model Reduces monoamine oxidase activity Rajeswari and Sabesan (2008)

VPA—Valproic acid; HDAC—histone deacetylase; EAE—experimental autoimmune encephalomyelitis; AD—Alzheimer's disease; HD—Huntingtons' disease; SAHA—Suberoylanilide hydroxamic acid; EAN—experimental autoimmune neuritis; KAT—lysine acetyltransferase; EAN—experimental autoimmune neuritis; PD-0 Parkinsons disease; TSA—Trichostatin A.

3. Epigenetic interference in animal models of MS

Animal models of MS are crucial for investigating the mechanisms underlying the disease as well as the design and testing of therapeutic strategies ( Van der Star et al., 2012 ). The autoimmune model of MS is experimental autoimmune encephalomyelitis (EAE) in which inflammation, myelin damage and neurodegeneration can be induced in susceptible animals following immunization with CNS proteins in a strong adjuvant. The course of disease, and histological and neurological signs heavily depend on the immunization regimen, as well as the strain and species of animal.

3.1. Experimental therapies targeting epigenetic processes

A potential role for epigenetic acetylation processes in disease pathogenesis emerges from several studies in EAE, including our own, and in experimental autoimmune neuritis (EAN, an animal model of inflammatory demyelinating peripheral neuropathies). A number of these studies are also summarized in Table 2 . In these studies the therapeutic potential of small molecule inhibitors that target the activities of the enzymes involved in modification of lysine residues in histones and non-histone proteins by acetylation has been evaluated. For instance, Camelo et al. showed that intraperitoneal administration of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) reduces spinal cord inflammation, demyelination, neuronal and axonal loss and ameliorates disability in the relapsing phase of EAE in C57BL/6 female mice ( Camelo et al., 2005 ). TSA treatment promoted neuronal survival and inhibited anti-inflammatory pathways leading to significant reduction in the cell infiltration in the CNS. The HDACi, vorinostat (SAHA), was shown to reduce neurological signs of EAE in C57BL/6 female mice ( Ge et al., 2013 ). In vitro studies revealed that mature DC-induced allogeneic T-cell responses and DC-derived Th1 and Th17 polarizing cytokines are reduced by exposure of DCs to vorinostat, possibly explaining the mechanism of action in EAE.

The therapeutic effect of the HDACi, valproic acid (VPA), on EAE in Lewis rats was revealed following daily administration, which greatly reduced the severity and duration of EAE ( Zhang et al., 2012 ). VPA administration also suppressed mRNA levels in spinal cords of the pro-inflammatory cytokines IFNγ, TNFα, IL-1β and IL-17, while an increase in the anti-inflammatory cytokine IL-4 was also noted. Preventive VPA treatment also greatly attenuated accumulation of macrophages and lymphocytes in EAE spinal cords while at the same time shifting the Th1 and Th17 profile to a Th2 and Treg profile ( Zhang et al., 2012 ).

VPA also reduces neurological disease in chronic relapsing EAE in Biozzi ABH mice as we have explored. As shown in Figure 3 intraperitoneally administration of VPA after induction of disease significantly delayed onset and severity of EAE in these mice.

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Figure 3 Therapeutic valproic acid (VPA) treatment attenuates onset and severity of EAE in Biozzi ABH mice. VPA inhibits the activities of class I and class IIa lysine deacetylases. (A) Animals were injected with 1 mg syngeneic spinal cord homogenate emulsified in CFA on days 0 and 7 ( Al-Izki et al., 2011 ). Animals were also injected intraperitoneally (i.p.) with 200 ng of pertussis toxin that was repeated 24 h later. Mice were injected i.p. daily with VPA (400 mg/kg in 200 μl PBS) or PBS from day 10 until day 24 after immunization. Clinical scores (0=normal, 1=limp tail, 2=impaired righting reflex, 3=hind-limb paresis, 4=complete hind-limb paralysis and 5=moribund/death) were measured daily post immunization. Animals were housed and monitored consistent with the principles of the ARRIVE guidelines as described previously (Baker and Amor, 2012 and Baker et al, 2011). (A) VPA treatment significantly delayed onset and severity of EAE. (B) Table detailing reduction in EAE score and day of onset.aMean ± SEM of maximum clinical score of EAE from all animals in the group.bMean ± SEM of maximum clinical score from animals exhibiting EAE within a group.cMean ± SD of day of onset of clinical disease. *p<0.05; **p<0.01.

The HDACi VPA and MS275 both attenuate the inflammatory reaction in EAN in Lewis rats resulting in a greatly reduced severity and duration of the disease (Zhang et al, 2008 and Zhang et al, 2010). VPA administration resulted in reduced mRNA levels in the lymph nodes of IFNγ, TNFα, IL-1β, IL-4, IL-6 and IL-17. At the same time FoxP3+ cells were increased but IL-17+ cells were decreased in peripheral blood and sciatic nerves ( Zhang et al., 2008 ). Administration of MS275 also resulted in a significant reduction in the transcript levels of the pro-inflammatory cytokines IFNγ, IL-1β and IL-17 in sciatic nerves ( Zhang et al., 2010 ). In lymph nodes, MS275 also depressed the expression of these cytokines but at the same time an increase in expression of the anti-inflammatory cytokine IL-10 and of FOXP3 was noted. In addition both drugs attenuated the accumulation of macrophages, T-cells and B-cells, and demyelination in sciatic nerves (Zhang et al, 2008 and Zhang et al, 2010).

By using the naturally occurring polyphenolic phytochemical curcumin, which inhibits the activity of lysine acetyltransferases (KATs), Xie et al. showed that clinical severity of EAE was significantly reduced in Lewis rats ( Xie et al., 2009 ). Moreover, it was revealed that curcumin treatment also affected the amount of inflammatory cells infiltration in the spinal cord. Interestingly, curcumin treatment resulted in a decrease of IL-17, TGFβ, IL-6, IL-21, STAT3 and RORγ expression, which had a bearing on differentiation and development of Th17 cells ( Xie et al., 2009 ).

Interference in SIRT's activities is also of interest as they play a key role in neuroprotection (recently reviewed by Albani et al., 2010 ). This is illustrated by the finding that Sirt1 activation by resveratrol confers neuroprotection in experimental optic neuritis ( Shindler et al., 2007 ). In addition, oral administration of resveratrol reduces neuronal damage in EAE in female SJL/J mice. However, in this model Sirt1 activation did not prevent inflammation ( Shindler et al., 2010 ).

In summary, the studies in experimental animal models demonstrate that small molecule inhibitors known to interfere in epigenetic acetylation processes modulate immune reactivity thereby suppressing systemic and local inflammation ameliorating disease. While Sirt activators do not seem to have an effect on inflammation, they clearly have neuroprotective properties. The promising observations made in these experimental animal models support the notion that interference in epigenetic processes might be a promising novel therapeutic option for treatment of MS.

3.2. Epigenetic interference in other inflammatory animal models

Similar studies in a number of other experimental disease models also reveal a critical role for epigenetic processes in onset and severity of disease (summarized in Table 2 ). As an example, in collagen-induced arthritis VPA, SAHA and MS-275 have anti-rheumatic activities and show a decrease in incidence and severity of disease amongst others by an increase in regulatory T cell function (Lin et al, 2007 and Saouaf et al, 2009). In collagen antibody-induced arthritis TSA suppresses synovial inflammation ( Nasu et al., 2008 ). In a mouse model of Alzheimers disease, VPA treatment was shown to have beneficial effect on disease severity by inhibiting Abeta production, neuritic plaque formation and behavioral deficits ( Qing et al., 2008 ). Also, in an animal model of cerebral amyloidosis for Alzheimer disease, MS-275 ameliorated neuroinflammation and cerebral amyloidosis ( Zhang and Schluesener, 2013 ). In other animal models such as for autoimmune lymphoproliferative syndrome (ALPS), renal injury, and experimental autoimmune prostatitis various HDACi were shown to display effective therapeutic potential (Dowdell et al, 2009, Noh et al, 2009, and Zhang and Schluesener, 2012).

Together, data from these various animal models reveals that interference in HDAC activities is very effective in ameliorating disease indicting that translational studies may very well show similar effects in humans.

4. Epigenetic dysregulation in Multiple Sclerosis

4.1. Histone acetylation patterns in MS

The question therefore remains whether in the human disease MS alterations in epigenetic processes can be observed. Indeed, in MS apparent changes in histone acetylation patterns in normal-appearing white matter (NAWM) and in early MS lesions have been documented ( Pedre et al., 2011 ). A shift towards histone acetylation in the white matter of the frontal lobes of aged subjects and in patients with chronic MS was observed. Furthermore, increased immunoreactivity for acetylated histone H3 in nuclei of mature (NogoA+) oligodendrocytes in a subset of MS samples was found ( Pedre et al., 2011 ). Previously it was shown that histone acetylation is associated with increased levels of transcriptional inhibitors of oligodendrocyte differentiation ( Li et al., 2009 ). The high level of histone acetylation observed in NogoA+ oligodendrocytes was associated with increased levels of transcriptional inhibitors of oligodendrocyte differentiation in female MS patients compared with non-neurological controls and correlated with disease duration. However, the opposite was true for early MS lesions where a marked reduction in oligodendrocyte histone acetylation was observed ( Pedre et al., 2011 ). Together, these observations reveal the fluidity of histone acetylation during the disease course resulting in increased levels of histone acetylation in NogoA+ oligodendrocytes at later stages of the disease.

The dynamics of global histone acetylation patterns in MS lesions and NAWM is underscored also by our unpublished observations, which are indicative of a increase in histone acetylation in NAWM of MS patients when compared with non-neurological controls ( Figure 4 A). Furthermore, altered histone acetylation patterns in NAWM and lesional areas in MS patients can also be observed ( Figure 4 B). Together, similar to other inflammatory autoimmune diseases, alterations in global levels of histone acetylation modifications can be observed. How these global alterations in histone acetylation or additional epigenetic histone and DNA modifications translate to transcription of specific genes involved in inflammation, oligodendrocyte differentiation or post-translation modification of non-histone gene products and the bearing this has on the function of their protein product will be discussed below.

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Figure 4 Expression of epigenetic markers in multiple sclerosis. (A) Enhanced display of the acetylated histone H4 mark (blue staining, upper panel) in pre-active lesions appearing in the NAWM of an MS patient ( Van der Valk and Amor, 2009 ). LN3 (HLA-DR) brown staining. (B) Nuclei displaying the acetylated histone H3 (Ac-H3) mark (brown staining). Left panel above: PLP staining revealing lesional area (L), an area of remyelination (R) and the NAWM (N). Right panel above: all nuclei in the NAWM display the Ac-H3 mark. In the lesional area only 60% of the nuclei display the Ac-H3 mark, while in the remyelinated area about 80% of the nuclei display the Ac-H3 mark (Bottom left and right panel, respectively). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

4.2. microRNAs in MS

In MS, by using whole blood, peripheral blood-derived lymphocytes or serum samples, several studies have shown differential expression of various miRNAs (reviewed inFenoglio et al, 2012, Huynh and Casaccia, 2013, Junker et al, 2011, and Thamilarasan et al, 2012). In particular miR-223 was found upregulated in blood and in Tregs from MS patients in comparison with healthy controls ( Keller et al., 2009 ). miR-223 modulates the NF-κB pathway and as such plays a central role inflammatory responses ( Li et al., 2010 ). In addition to miR-223, profiling in MS lesions revealed the upregulation of miR34a, miR-155 and miR-326 in active lesions when compared to normal brain white matter ( Junker et al., 2009 ). Since miR34a, miR-155 and miR-326 target CD47 these observations suggest that in MS lesions CD47 is reduced in brain resident cells, releasing macrophages from inhibitory control, thereby promoting phagocytosis of myelin ( Junker et al., 2009 ). miR-155 together with miR-338 and miR-491 were also found to be up-regulated in cerebral white matter of MS patients ( Noorbakhsh et al., 2011 ). As a result levels of important neurosteroids were suppressed in white matter of MS patients. These observations are in support of dysregulated miRNA levels in MS ( Koch et al., 2013b ). Further studies are required to establish the potential role for these miRNAs in MS pathogenesis.

4.3. Gene-specific chromatin alterations in the CNS and in MS

As discussed in the previous section, alterations in global levels of histone acetylation in NogoA+ oligodendrocytes has a bearing on the levels of transcriptional inhibitors of oligodendrocyte differentiation ( Pedre et al., 2011 ). This is particularly revealed by chromatin immunoprecipitation (ChIP) showing that the promoter of the TCF7L2 gene, which plays a critical role in modulating oligodendrocyte differentiation, displays an increase in histone acetylation in chromatin encompassing the TCF7L2 gene promoter in MS in comparison to controls ( Pedre et al., 2011 ).

That epigenetic post-translational modifications impact on disease is supported by the demonstration that in MS white matter hypomethylation of the promoter of the peptidyl arginine deaminase 2 (PAD2) gene is correlated with an increase in the levels of PAD2 expression (Mastronardi et al, 2007 and Moscarello et al, 2007). The PAD2 enzyme catalyzes MBP citrullination and increased levels of citrullinated myelin basic protein (MBP) can result in a loss of myelin stability in MS brains ( D’Souza et al., 2005 ).

With respect to immune genes, increased expression of MHC class I and class II molecules is noted in various types of lesions in MS, when compared with NAWM ( Gobin et al., 2001 ). Expression of both classes of MHC genes is also determined by epigenetic processes. In particular because the transcriptional co-activators which play an important role in the transcriptional activation of these genes act as platforms for the recruitment of histone modifying activities for adequate expression (Kobayashi and van den Elsen, 2012 and Van den Elsen et al, 2004).

Furthermore, it is now firmly established that remyelination is controlled by the activities of enzymes that modify histones by acetylation ( Shen et al., 2008 ).

5. Epigenetic dysregulation in other neurodegenerative disorders

In addition to MS, it has become apparent in recent years that epigenetic dysregulation is also frequently observed in other neurodegenerative disorders including Alzheimer disease, Huntington's disease, Parkinson's disease, ischemia, mood disorders (depression and anxiety), neurodevelopmental disorders (Rubinstein–Taybi syndrome, Rett syndrome, Fragile X syndrome), Immunodeficiency with Centromeric Instability and Facial anomalies (ICF) syndrome, Angelman and Prader–Willi syndromes, and in inflammatory disorders (reviewed inAbel and Zukin, 2008, Chuang et al, 2009, De Greef et al, 2011, Lalande and Calciano, 2007, Urdinguio et al, 2009, and Wierda et al, 2010). For example, Angelman and Prader-Willi syndromes are recognized by DNA methylation imprinting defects encompassing human chromosome 15q11-q13, which affect allele-specific expression in the brain of disease-associated genes ( Lalande and Calciano, 2007 ). In Rubinstein–Taybi syndrome the genetic defect is in the transcriptional co-activator CREB-binding protein (CBP), which possesses lysine acetyltransferase activities ( Petrij et al., 1995 ). ICF1 syndrome is recognized by mutations in DNMT3b ( Xu et al., 1999 ), while in ICF2 the mutations are in the zinc-finger- and BTB (bric-a-bric, tramtrack, broad complex)-domain-containing 24 (ZBTB24), which belongs to a large family of transcriptional repressors ( De Greef et al., 2011 ). Both ICF1 and ICF2 patients share the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences (De Greef et al, 2011 and Weemaes et al, 2013). Loss of function mutations in MeCP2 is characteristic for RETT syndrome ( Amir et al., 1999 ).

Early life experiences seem to determine anxiety-mediated behaviors and disorders later in life. These events are mediated by epigenetic processes which is illustrated by the observation that maternal care influences methylation of the glucocorticoid receptor (GR) at promoter CpG residues in the hippocampus is. Early in life pup licking and grooming, and arched-back nursing were found to influence the methylation status of the GR in the hippocampus. These alterations in DNA methylation were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter and ultimately affected the hypothalamic-pituitary-adrenal (HPA) responses to stress in the offspring ( Weaver et al., 2004 ). TSA treatment eliminates maternal effect on histone acetylation and NGFI-A binding ( Weaver et al., 2004 ). Moreover, treatment of the offspring with TSA also reverses the early-in-life induced maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring in adulthood ( Weaver et al., 2006 ).

6. Conclusions and perspectives

Epigenetic control of gene expression and maintenance of cellular identity is one of the most fundamental regulatory systems within the cell. Not surprisingly it fulfils essential roles in processes involved CNS homeostasis. Disturbances of the delicate interplay between the various activities that modify histones (and also non-histone targets) may lead to cellular dysfunction as observed in pathological conditions. In the case of MS this contributes to the neuro-inflammatory and neuro-degenerative character of the disease. Intervention in epigenetic gene regulation in disease states might prove to be a beneficial therapeutic option for the near future, especially in complex multi-factorial diseases such as MS. Epigenetic interference in the treatment of MS may be targeted at relevant immune components such as dendritic cells, Tregs and Th17 cells, or cells of the CNS such as microglia, neurons or astrocytes ( Figure 5 ). However, caution should be taken as most of the currently available drugs display a broad spectrum of activity, which could lead to severe side-effects thereby limiting their clinical efficacy. Additionally, in case of MS, most-likely simultaneous targeting of the CNS and the peripheral immune system is required to obtain the desired clinical efficacy. In that case these inhibitors should also be able to cross the blood-brain barrier. Therefore, further studies are required to identify the histone and DNA modifying activities, and epigenetic effectors displaying altered expression characteristics and protein function in MS. The identification of MS-associated epigenetic activities allows the design of more specific drugs, which can be evaluated for their clinical efficacy.

gr5

Figure 5 Therapeutic potential of inhibitors of epigenetic processes in the treatment of multiple sclerosis. Epigenetic drugs such as histone deacetylase inhibitors, lysine acetyltransferase inhibitors or DNA demethylating drugs have the capacity to rescue the distorted epigenetic processes that affect the expression of genes in MS. In this way these drugs mediate peripheral immunosuppressive activities either through skewing of dendritic cell function, or directly by inhibiting the activities of Th1/Th17 cells or by promoting the activities of Tregs. At the same these drugs may also exhibit neuroprotective properties or interfere in disease-associated pathogenic processes in astrocytes or microglia.

In summary, the results from various preclinical studies indicate that epigenetic therapy by using inhibitors that target disease-associated components of the epigenetic machinery may prove to be beneficial in the treatment of MS.

Conflicts of interest

The authors declare no conflicts of interests.

Acknowledgments

We apologize to our colleagues whose work was not cited in this review. The authors greatly acknowledge the support of the MS Research Foundation of the Netherlands, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society USA and the National Center for the Refinement, Reduction and Replacement of Animals in Research.

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Footnotes

a Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

b Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

c Neuroscience and Trauma Centre, Blizard Institute, Barts and the London School of Medicine and Dentistry, QJ;Queen Mary University of London, London, United Kingdom

lowast Correspondence to: Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel.: +31 20 444 2898.