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The Epigenetic Face of Systemic Lupus
Erythematosus
Esteban Ballestar, Manel Esteller and Bruce C. Richardson
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References
J Immunol 2006; 176:7143-7147; ;
doi: 10.4049/jimmunol.176.12.7143
http://www.jimmunol.org/content/176/12/7143
OF
THE
JOURNAL IMMUNOLOGY
BRIEF REVIEWS
The Epigenetic Face of Systemic Lupus Erythematosus1
Esteban Ballestar,2* Manel Esteller,* and Bruce C. Richardson†
A
lthough the existence of a genetic determinant of
many diseases is well established, it is generally accepted that environmental factors, including diet and
lifestyle, modulate the susceptibility, in part, through epigenetic changes (1). However, although many studies have corroborated these ideas and led to the identification of the genetic
defects involved in many diseases, virtually no epigenetic information has been routinely or systematically collected at the genome level. In recent years, we have witnessed an increasing interest in the role of epigenetic modifications in the etiology of
human disease.
Epigenetics determines the identity and function of cells
Epigenetics comprises the stable and heritable (or potentially
heritable) changes in gene expression that do not entail a change
in DNA sequence. Whereas genetic information is homogeneous in an organism regardless of the cell type (excepting differences due to somatic mutations), epigenetic modifications
*Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National
Cancer Centre (CNIO), Madrid, Spain; and †Department of Medicine, University of
Michigan, Ann Arbor, MI 48109
Received for publication March 14, 2006. Accepted for publication March 31, 2006.
The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
1
This work was supported by Grants BFU2004-02073/BMC (Ministerio de Ciencia
y Tecnologia) and GR/SAL/0224/2004 (Government of Madrid), the Ramon y Cajal
Copyright © 2006 by The American Association of Immunologists, Inc.
are characteristic of different cell types and, in fact, play a key
role in defining the transcriptome, which determines the identity of each cell type (2).
Two major groups of changes contribute to defining the epigenome of a cell: DNA methylation and histone modifications.
The most common form of DNA methylation occurs at the
5⬘ position of cytosine in the context of CpG dinucleotides,
which are unevenly distributed throughout the genome. Particularly remarkable are CpGs clustered in so-called CpG islands
(3), many of which coincide with the promoter of protein-protein-coding genes, as well as those present in repetitive sequences. CpG methylation has functional consequences, such
as transcriptional repression, when it occurs in CpG islands. In
fact, a number of tissue-specific genes are silenced by promoter
methylation.
Posttranslational modifications that occur in histones make
up a second group of epigenetic modifications. Core histones
are organized in octamers that are intimately associated with
DNA in nucleosomes, the repeating subunit of chromatin. Lysine acetylation and methylation and serine phosphorylation,
among other modifications, regulate many nuclear functions.
For instance, reversible acetylation of histone lysines is generally
associated with transcriptional activity. The functional consequences of lysine or arginine methylation depend on the specific site that is modified. Recently, it has been proposed that
different combinations and sequences of posttranslational
modifications make up a sort of code that is read by nuclear
factors to mediate different processes (4).
DNA methylation and histone modifications are coupled
through different machineries, including DNA methyltransferases (DNMTs)3 and different families of methylated DNA
binding proteins that associate with histone modifying enzymes
in multiprotein complexes (5) (Fig. 1).
Besides a direct effect on nuclear processes such as transcriptional activity, DNA methylation and histone modifications
also play a key role in organizing nuclear architecture (6, 7),
which in turn is also involved in regulating transcription and
other nuclear processes. Therefore, epigenetic modifications are
essential for defining the cellular transcriptome at several levels.
Aberrant changes in the pattern of epigenetic modifications
Programme, Public Health Service Grant AR42525, and a merit grant from the Veterans Administration.
2
Address correspondence and reprint requests to Dr. Esteban Ballestar, Cancer Epigenetics Laboratory, Molecular Pathology Programme, CNIO, C/ Melchor Fernandez Almagro
3, 28029 Madrid, Spain. E-mail address: [email protected]
3
Abbreviations used in this paper: DNMT, DNA methyltransferase; ICF, immunodeficiency, centromeric region instability, and facial anomaly; SLE, systemic lupus erythematosus; HAT, histone acetyltransferase.
0022-1767/06/$02.00
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Systemic lupus erythematosus (SLE) is an archetypical systemic, autoimmune inflammatory disease characterized
by the production of autoantibodies to multiple nuclear
Ags. Apoptotic defects and impaired removal of apoptotic
cells contribute to an overload of autoantigens that become available to initiate an autoimmune response. Besides the well-recognized genetic susceptibility to SLE, epigenetic factors are important in the onset of the disease, as
even monozygotic twins are usually discordant for the disease. Changes in DNA methylation and histone modifications, the major epigenetic marks, are a hallmark in genes
that undergo epigenetic deregulation in disease. In SLE,
global and gene-specific DNA methylation changes have
been demonstrated to occur. Moreover, histone deacetylase
inhibitors reverse the skewed expression of multiple genes
involved in SLE. In the present study, we discuss the implications of epigenetic alterations in the development and
progression of SLE and how epigenetic drugs constitute a
promising source of therapy to treat this disease. The
Journal of Immunology, 2006, 176: 7143–7147.
7144
BRIEF REVIEWS: THE EPIGENETIC FACE OF SLE
lifetime (14, 15). In fact, the comparison of epigenetic modifications in genetically identical monozygotic twins has revealed
that environmental factors, including diet and lifestyle, contribute significantly to the phenotype by changing the epigenetic
profile. This could explain discordance in the development of
disease (15). Individual epigenetic peculiarities that modulate
susceptibility could therefore explain the apparent complexity
in the patterns of inheritance.
The role of apoptosis in systemic lupus erythematosus (SLE)
would result in altered nuclear activity, and thereby an altered
transcriptome, which would transform the identity of the cell.
In recent years, increasing evidence has demonstrated the role
of epigenetic alterations in the etiology of many diseases. For
instance, unscheduled hypermethylation of CpG islands of tumor suppressor genes and the resulting transcriptional silencing
are associated with malignant transformation in cancer (8).
These changes are associated with aberrant patterns of histone
modifications (9). In addition, cancer cells suffer a loss of methylation and alterations in the histone modification pattern of
repetitive sequences that appear to be involved in chromosomal
instability in cancer (10, 11). Other diseases with well-recognized epigenetic defects include immunodeficiency, centromeric region instability, and facial anomalies (ICF) syndrome,
caused by mutations in the DNMT 3B, Prader-Willi and Beckwith-Wiedemann syndromes, resulting from the absence of
transcriptional regulation of the paternal or maternal copy of an
imprinted gene, and Rett syndrome, involving mutations in the
methylation-dependent transcriptional repressor MeCP2 (12,
13). The epigenetic component of many other diseases remains
to be identified. In fact, the epigenetic framework could explain
several characteristics of many diseases, including their age dependence and quantitative nature, and the mechanism by
which the environment modulates genetic predisposition to
disease (1). Moreover, recent findings have indicated that epigenetic alterations accumulate gradually over an individual’s
FIGURE 2. Scheme depicting the model of the two major alterations in SLE
patients in association with epigenetic events that explain the presence of autoantibodies: increased rate of apoptosis in circulating lymphocytes and abnormal
recognition of nuclear autoantigens released during apoptosis. The box on the
right side includes epigenetic events that are proposed to participate in SLE.
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FIGURE 1. Interconection between epigenetic modifications. An array of
nucleosomes corresponding to a promoter CpG island is shown. Histone octamers are represented by gray circles. DNA is represented as a red line in which
only methylated CpG dinucleotides are shown (as red circles). Acetylated histone tails are lines protruding from octamers, whereas deacetylated histone tails
are not shown. Changes in the chromatin of these genes lead to a change in the
transcriptional status. Demethylation is compatible with gene transcription
(top) and methylation leads to gene silencing. A number of nuclear factors associate with the methylated promoter: DNMTs and methyl-CpG binding domain proteins (MBDs) that associate with histone methyltransferases (HMT
K9 H3) and histone deactylases (HDACs). Histone methyltransferases (HMT
K4 H3) and histone acetyltransferases (HATs) are associated with unmethylated promoters and transcriptional activity (top).
A remarkable example of a disease for which patterns of inheritance are extremely complex is SLE, an autoimmune disease
characterized by the production of a variety of Abs against nuclear components that causes inflammation and injury of multiple organs. The disease primarily affects women in their reproductive years, and its prevalence is estimated to vary between
12 and 64 cases per 100,000 in European-derived populations
and to be higher in non-European-derived populations. The
presence of autoantibodies directed against a set of cell constituents has meant that lupus is classified as an autoimmune disease. In fact, autoantibodies to nuclear components, including
nucleosomes, and their individual components, DNA and histones, are typically present years before the diagnosis of SLE and
progressive accumulation precedes the onset of the disease (16).
Several studies indicate that the presence of autoantibodies in
SLE patients is associated with two major alterations: increased
rate of apoptosis in circulating lymphocytes and monocytes,
and abnormal recognition of autoantigens released during apoptosis (Fig. 2).
Nucleosomes are released in vivo exclusively by endonuclease
digestion of chromatin during apoptosis (17), and therefore, acceleration of this type of cell death, or an impaired clearance of
apoptotic cells, provides a mechanism for disrupting peripheral
self-tolerance. The current dogma is that clearance of intact dying cells prevents secondary necrosis of apoptotic cells and release of dangerous enzymes into the microenvironment and is
therefore anti-inflammatory. However, recent findings have
The Journal of Immunology
Epigenetic alterations in SLE: DNA methylation changes
As mentioned above, DNA methylation is a fundamental determinant of chromatin structure, with potent suppressive effects on gene expression. Abnormalities in the DNA methylation system result in the aberrant increase or decrease in gene
expression, which is implicated in the development of a variety
of diseases. The first evidence of the role of aberrant changes in
the DNA methylation patterns in the development of SLE was
that T cells from patients with active lupus were shown to exhibit globally hypomethylated DNA (27). More recent studies
have demonstrated an association between DNA hypomethylation in SLE and a decrease in the enzymatic activity of
DNMTs (28), implying a possible mechanism to explain DNA
hypomethylation. Additional evidence of the role of methylation changes in the development of SLE comes from studies
with DNA demethylating drugs. One of the most common
demethylating drugs used to induce SLE in mice is 5-azacytidine, a cytosine analog that contains a nitrogen atom at the 5⬘
position of the pyrimidine ring and is incorporated into newly
synthesized DNA. Treatment with 5-azacytidine causes genome-wide hypomethylation, resulting in the altered expression of many genes. Other demethylating drugs used to induce
SLE are procainamide (29), a competitive DNMT inhibitor,
and hydralazine, whose demethylating activity has been explained as an indirect result of the inhibition of the ERK pathway signaling, decreasing DNMT1 and DNMT3a levels during mitosis (30). In all cases, exposing T cells to demethylating
drugs results in the demethylation-dependent induction of lupus-like disease (31–34).
The mechanisms by which hypomethylated T cells induce
SLE are not very well understood. The effects of drug-induced
DNA demethylation have been studied in T cell Ag recognition, B cell help, and T macrophage interactions. The most
striking effect is that T cells become responsive to normally subthreshold stimuli and autoreactivity. It has been described that
demethylated lupus T cells overexpress integrin adhesive receptors such as LFA-1 (CD11a/CD18) (35, 36). Overexpression of
LFA-1 overexpression has been demonstrated to have a direct
effect on autoreactivity (34).
The identification of genes that are deregulated through
DNA methylation changes in SLE contributes to our understanding of the pathway of the disease. However, the full repertoire of genes affected is not known. Recently, specific promoter demethylation of several genes has been shown to
contribute to aberrant overexpression of various genes. These
aberrant changes occur in genes like perforin (37), whose demethylation could contribute to monocyte killing. CD70 is
also overexpressed in CD4⫹ lupus T cells by demethylation
(38). In this case, CD70 overexpression contributes to excessive
B cell stimulation in lupus. Another example is the demethylation of ITGAL regulatory sequences, which may also contribute to the development of lupus (39).
Systematic analysis of methylation and demethylation events
in different stages and the extent of SLE manifestation will
surely contribute to our understanding of the hierarchy and relevance of these methylation events in the development of SLE.
Histone modifications in SLE
As with the role of DNA methylation alterations in SLE, our
knowledge about the alterations in the histone modification
patterns in SLE is incomplete. Since DNA methylation and histone modifications are mechanistically linked (see Fig. 1), it is
likely that different changes in histone modifications are associated with DNA methylation changes in SLE.
Similarly to studies on DNA methylation and lupus, most of
the evidence about the role of changes in histone modifications
in SLE comes from the use of epigenetic drugs. In the case of
histone modification, the use of histone deacetylase inhibitors
suggests that deacetylation is involved in the skewed expression
of certain genes that are associated with the disease.
For instance, SLE Th cells exhibit increased and prolonged
expression of cell-surface CD40L (CD154), spontaneously
overproduce IL-10 (IL-10), but underproduce IFN-␥ (IFN-␥).
The histone deacetylase inhibitor trichostatin A (TSA) significantly reverses this skewed expression of these gene products
(40). It is likely that this reversion is the result of modification of
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suggested that, under special circumstances, cells dying by apoptosis may also trigger a specific immune response (18, 19). Indeed, dying cells are capable of triggering the release of chemokines and proapoptotic molecules by macrophages. Apoptosis
under certain conditions appears to be proinflammatory, triggering the caspase-1-mediated release of inflammatory cytokines from dying cells (20).
In vitro, apoptotic material has been demonstrated to activate
T cells and B cells. In fact, coincubation of autologous apoptotic material with freshly isolated PBMCs leads to the expansion
of histone-specific T cell clones that could help B cells to
form Abs.
The loss of immune tolerance to self-components is the basis
of SLE, so many genes encoding proteins with regulatory or
adaptive functions in the immune system have been considered
as candidates predisposing to development of the disease (21).
These include genes of the MHC, Fc␥Rs, complement components, CTL Ag-4, and programmed cell death-1. Moreover, the
analysis of polymorphisms suggests that, besides gene-gene interactions, many modifying environmental effects influence the
disease phenotype.
An interesting line of evidence that environmental factors influence the development of SLE comes from studies of identical
monozygotic twins. The highest estimated concordance rate in
twins is ⬍60% (22, 23), so the involvement of nongenetic factors in the pathogenesis of SLE must be invoked. As mentioned
above, epigenetic alterations are accumulated during an individual’s lifetime (15). The high incidence of twin pairs in which
only one of the siblings has developed SLE supports the notion
that environmental factors and their involvement in epigenetic
modifications could affect the onset of the disease. Epigenetic
alterations could influence the onset of SLE at several levels.
The first is the epigenetic deregulation of genes that contribute
to, or increase the activation of, apoptosis. Moreover, apoptotic-released nuclear material with specific epigenetic patterns
(24) may act more efficiently as an autoantigen. In addition,
epigenetic alterations may contribute to an exacerbated activation of T and B cells. These mechanisms are not exclusive.
The use of expression microarrays is an interesting approach
to identifying targets of transcriptional deregulation in SLE patients. By this strategy, deregulated expression in genes of the
IFN pathway was identified (25). Some of these genes are
known to be deregulated by epigenetic mechanisms (26). The
following sections present some of the evidence of epigenetic
alterations in SLE.
7145
7146
the histone acetylation status, although alteration of the acetylation levels of transcription factors cannot be discarded. At any
rate, this result not only suggests that histone acetylation might
account for this aberrant expression but also that this pharmacological agent may be a candidate for the treatment of this autoimmune disease.
Similar results have been obtained with other histone
deacetylase inhibitors, such as suberoylanilide hydroxamic acids, that are able not only to revert the aberrant expression of
certain genes but also to modulate renal disease (41).
Detailed information is therefore needed about the type and
extent of histone modifications at the global and gene-specific
scales in SLE T cells. This information will not only serve to
identify genes that suffer aberrant deregulation but also help to
develop specific epigenetic drugs.
Toward a definition of SLE as an epigenetic disease: perspectives and
therapies
and reminiscent of the signaling aberrations that have been described in patients with SLE. However, histone deacetylase inhibitors and DNA-demethylating drugs could also be a promising source of epigenetic therapies to treat SLE. Current
evidence indicates that most of the genes that exhibit aberrant
patterns of DNA methylation are hypomethylated, although
gene-gene-specific hypermethylation cannot be ruled out.
Therefore, a detailed analysis of DNA methylation at the gene
level will serve to evaluate how useful DNA demethylating
drugs could be.
In addition, increasing efforts are being made with other
compounds with histone methyltransferase inhibiting activity,
which could also be useful in epigenetic therapy.
We truly believe that the future in the treatment of SLE depends greatly on the ability to revert epigenetic alterations,
which are in fact the factors that determine that a genetically
prone individual actually develops the disease or not. In this
sense, the precise determination of the array of epigenetic alterations on a gene-gene-specific level is absolutely required. In
parallel, the generation of compounds able to revert or modify
epigenetic patterns in a gene-targeted fashion will ensure the
development of effective therapies to cure SLE.
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Many approaches have been used with partial success to determine the genetic determinants of SLE, including analyses based
on candidate genes, genome-wide linkage studies, and familybased classical linkage studies. All the evidence points to the existence of a complex system in which multiple genes may participate in the determination of SLE predisposition. However,
since epigenetics could play a key role in defining or modulating
the onset of the pathogenesis for genetically predisposed individuals, it is of inherent interest to analyze epigenetic modifications systematically to understand the etiology of SLE. This will
surely help not only to elucidate the pathway of the disease but
also to determine whether epigenetic therapies can be used to
treat or prevent the disease.
A number of analytical techniques are now available for
studying epigenetic modifications in a genome-wide manner.
These techniques have already proved to be useful for identifying epigenetic alterations in other diseases, such as various types
of cancer. These include methods that identify changes in the
methylation profile of specific sequences, such as differential
methylation hybridization or amplification of intermethylated
sites (42). Both techniques are based on the use of restriction
endonucleases that are sensitive to methylation status followed
by hybridization on genomic microarrays or sequencing and database analysis. Other techniques, such as chromatin immunoprecipitation assays coupled to hybridization of genomic microarrays (ChIP-on-chip) (9), allow the identification of
sequences with different patterns of histone modifications. The
systematic use of these genomic techniques will serve to provide
a full profile of epigenetic deregulation in SLE.
Unlike genetic alterations, which are permanent, epigenetic
alterations are reversible. This opens up the possibility of using
epigenetic drugs to reverse the pattern of epigenetic alterations
to relieve the phenotype. To exploit potential it is important to
define the full range of epigenetic modifications in SLE.
Several drugs that reverse the pattern of epigenetic modifications have already been used to treat SLE. To date, histone
deacetylase inhibitors such as suberoylanilide hydroxamic acid
and TSA have proved to be useful for relieving SLE disease in
mice (26). For instance, TSA suppresses the expression of the
TCR ␨-chain gene, whereas it up-regulates the expression if its
homologous gene Fc(␧)RI ␥-chain. On the other hand, TSA
suppresses the expression of the IL-2 gene (43). The effects of
TSA on human T cells are predominantly immunosuppressive
BRIEF REVIEWS: THE EPIGENETIC FACE OF SLE
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