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Department of Medicine, University of Michigan and the Veterans Affairs Hospital, Ann Arbor, MI 48109-0940
3To whom correspondence should be addressed. E-mail: brichard{at}umich.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONLITERATURE CITED |
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KEY WORDS: • aging • lupus • carcinogenesis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONLITERATURE CITED |
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,2
). However, DNA methylation patterns are not fixed. The patterns can change, causing alterations in gene expression that may contribute to autoimmunity, aging and carcinogenesis. This article will review the evidence for methylation changes in fully differentiated cells and their functional significance. Possible mechanisms contributing to the methylation changes also will be reviewed. However, because the mechanisms causing these changes are not well characterized, it is hoped that this review will prompt further studies on the mechanisms altering methylation patterns in mature cells. Autoimmunity
Model systems.
Evidence suggesting that DNA methylation might contribute to autoimmunity first came from studies on DNA methylation in T lymphocytes. Early experiments showed that treating antigen-specific CD4 T cells with the DNA methylation inhibitor 5-azacytidine (5-azaC) induced autoreactivity. The 5-azaC–treated cells responded to self class II major histocompatibility complex (MHC) molecules lacking the relevant antigen for a period of 1–2 wk, before reverting to antigen reactivity (3
). The autoreactivity correlated with overexpression of lymphocyte function-associated antigen-1 (LFA-1) and was due to effects on CD11a but not CD18 transcription (4
,5
). Inducing LFA-1 overexpression by transfection caused an identical autoreactivity (6
,7
) confirming a role for LFA-1 overexpression in the autoreactive response. More recent studies have shown that hypomethylation of sequences flanking the ITGAL promoter, encoding CD11a, contribute to the overexpression (Lu, Q.-J., Kaplan, M., Ray, D., Zacharek, S., Gutsch, D. & Richardson, B., unpublished results).
The observation that a relatively simple chemical treatment could cause autoreactivity in normal lymphocytes suggested that a similar mechanism might contribute to autoimmunity in vivo. This was tested by treating normal murine T cells with 5-azaC then injecting the autoreactive cells into syngeneic recipients. Mice receiving treated but not untreated cells developed anti-DNA antibodies and histologic evidence of autoimmunity that most closely resembled human lupus (8
,9
). T cells made autoreactive by transfection with LFA-1 caused a similar disease, supporting a role for LFA-1 overexpression in the disease process (7
). These experiments suggested that impaired T cell DNA methylation might contribute to the development of lupus-like diseases and prompted studies in lupus patients.
Human lupus.
Initial studies demonstrated that T cells from patients with active lupus had globally hypomethylated DNA. The hypomethylation correlated with decreased DNA methyltransferase enzyme activity and Dnmt1 mRNA, providing a mechanism for the DNA hypomethylation (10
,11
). Mechanisms that might contribute to decreased DNA methyltransferase expression were sought. Dnmt1 levels normally increase following mitogenic T cell stimulation (12
), and inhibiting either the c-jun NH2-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK) pathways will decrease Dnmt1 expression (11
,13
), so signaling was examined. Lupus T cells were found to have intact JNK pathway signaling, but ERK pathway signaling was decreased, and the magnitude of the defect was directly proportional to disease activity. Inhibiting normal T cell ERK pathway signaling with the selective mitogen-activated protein/extracellular signal-regulated-kinase (MEK) inhibitor PD98059 decreased T cell Dnmt1 mRNA and enzyme activity to the extent seen in lupus and induced DNA hypomethylation, indicating that the decrease in lupus patients had functional significance (11
).
Because LFA-1 overexpression is important in the animal model of lupus and T cells from lupus patients are similarly hypomethylated, LFA-1 expression was examined. T cells from patients with active lupus were found to selectively overexpress LFA-1 on an autoreactive T cell subset, similar to 5-azaC–treated cells, and the extent of the overexpression was directly related to disease activity (4
). Bisulfite sequencing demonstrated that the same sequences flanking the ITGAL promoter are demethylated in 5-azaC–treated T cells as in T cells from patients with active lupus, and patch methylation of this region in ITGAL reporter constructs demonstrated that methylation decreased transcription (Lu, Q.-J., Kaplan, M., Ray, D., Zacharek, S., Gutsch, D. & Richardson, B., unpublished results). These results provide evidence linking hypomethylation of specific sequences to LFA-1 overexpression in the model system and human lupus. Because LFA-1 overexpression is sufficient to cause a lupus-like disease (7
), these studies support the hypothesis that DNA hypomethylation contributes to the pathogenesis of human lupus.
Treating normal T cells with DNA methylation inhibitors is sufficient to cause a lupus-like disease in animal models, so exposure to exogenous DNA methylation inhibitors might similarly contribute to the development of autoimmunity. In support of this, the two drugs most frequently implicated in causing a lupus-like disease, procainamide and hydralazine, have been reported to inhibit DNA methylation, cause LFA-1 overexpression and induce autoreactivity in human and murine T lymphocytes (6
,14
,15
). Ultraviolet (UV) light, which triggers lupus flares, also inhibits DNA methylation, increases LFA-1 expression and induces autoreactivity (6
). In addition, murine T cells treated with procainamide or hydralazine cause a lupus-like disease identical to that induced by 5-azaC (15
), and procainamide demethylates the same ITGAL promoter-flanking region as does 5-azaC and as occurs in human lupus (Lu, Q.-J., Kaplan, M., Ray, D., Zacharek, S., Gutsch, D. & Richardson, B., unpublished results). Procainamide is a competitive inhibitor of DNA methyltransferase enzyme activity (16
). In contrast, hydralazine decreases Dnmt1 and Dnmt3a by inhibiting T cell ERK pathway signaling similar to PD98059 (Deng, C., Zhang, Z., Attwood, J. & Richardson, B., unpublished results).
Together these studies indicate that DNA hypomethylation, caused by decreased ERK pathway signaling or DNA methyltransferase inhibition, and affecting expression of molecules including LFA-1, may contribute to the pathogenesis of both drug-induced and idiopathic human lupus.
Aging
The evidence demonstrating age-dependent changes in DNA methylation is relatively more extensive. In general, total genomic deoxymethylcytosine (dMC) levels decrease with aging in most vertebrate tissues. Demethylation has been documented in aging salmon, mice, rats, cows and humans and occurs in the brain, liver, small intestine mucosa, heart, spleen and T lymphocytes (17
–21
). In contrast, rat lung DNA does not appear to demethylate, and global dMC content in rat kidneys increases (19
). In one report, splenic DNA demonstrated the greatest interindividual variability in dMC content (17
), an observation that may have relevance to age-dependent changes in immune function (vide infra).
A subset of genes changes methylation status with aging in a tissue-specific fashion. For example, the ß-actin gene appeared to be demethylated with age in rat spleen but not brain or liver tissue, but the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene or the rat brain glial fibrillary acidic protein gene (23
) does not change methylation status in either of these organs (22
). The c-myc gene demethylates with age in murine spleens, but some cytosine guanine dinucleotides (CpGs) in this gene hypermethylate with aging in the liver (24
). c-fos methylation increases in the liver but not in the brain or spleen (25
). Numerous other genes but clearly not all also change methylation status with aging in the brain, liver and spleen [for reviews, see Ono et al. (25
)]. Changes also occur outside of coding regions: repetitive DNA sequences in brains from aged rats contain greater amounts of dMC than identical sequences from younger rats (26
). Retroviral elements also demethylate with age, which may contribute to their increased expression in tissues of aged donors (27
,28
). However, in many of these reports changes in promoter methylation were not measured, and the transcriptional relevance of the changes was not determined.
One T cell gene product that increases with age is LFA-1 (CD11a/CD18) (29
). CD11a mRNA also increases with age, and the ITGAL promoter 5'-flanking region demethylates (Zhang, Z., Lu, Q.-J., Deng, C. & Richardson, B., unpublished results), similar to the changes identified in lupus (Lu, Q.-J., Kaplan, M., Ray, D., Zacharek, S., Gutsch, D. & Richardson B., unpublished results). Because patch methylation studies have confirmed the transcriptional relevance of methylation changes in this region (Lu, Q.-J., Kaplan, M., Ray, D., Zacharek, S., Gutsch, D. & Richardson B., unpublished results), this example provides evidence for age-dependent hypomethylation affecting the expression of a tissue-specific gene lacking a CpG island. People develop antinuclear antibodies and other features of autoimmunity with aging (30
), so these methylation changes may contribute to some forms of autoimmunity that occur in the elderly.
Methylation changes also occur in CpG islands, affecting expression of the associated gene. For example, the CpG island associated with the human estrogen receptor has been observed to be hypermethylated with aging in colonic mucosa (31
). A similar change occurs during neoplastic transformation, and introduction of an unmethylated exogenous gene into colon carcinoma cells suppresses growth, suggesting that aberrant methylation could predispose to malignancy (31
). Another report from the same group demonstrates similar age-dependent methylation of the CpG island associated with the insulin-like growth factor 2 (IGF2) gene, which also displayed a decrease in expression (32
). More recently, methylated CpG island amplification was used to show that 19 of 30 cloned CpG islands from normal colonic mucosa methylate with age (33
). Age-dependent changes in CpG island methylation have been reported in other tissues as well [for reviews, see Toyota et al. (33
)].
Our group has used restriction landmark genome scanning (RLGS) to examine CpG island methylation in human T cells. Initial studies demonstrated that approximately 15% of the CpG islands are variably methylated on a clonal basis in middle-aged donors and that methylation correlates with the level of expression of the associated gene (34
). RLGS analysis of T cells from newborns, middle-aged and old individuals has identified 29 islands that change methylation status with aging, with 23 becoming methylated, and 6 appearing to be demethylated. One of the 23 CpG islands that become methylated with age is associated with the gene encoding the transcription regulator forkhead, and forkhead transcripts decreased with age, again demonstrating functional significance for these methylation changes (unpublished results). These results, together with experiments demonstrating that loci in specific tissues demethylate during aging whereas others hypermethylate, argue strongly that methylation patterns change with age, with both methylation and demethylation occurring. These reports also demonstrate that age-dependent changes in methylation can have functional significance.
As noted above, age-dependent changes in T cell DNA methylation may contribute to the development of some forms of autoimmunity in the elderly. With aging, T lymphocytes also develop well-characterized changes in function and gene expression, which include an increase in the memory subset, decreased interleukin-2 (IL-2) production and decreased responsiveness to antigenic stimuli, collectively termed immune senescence (35
). Age-dependent changes in DNA methylation could contribute to this process. As one test of these hypotheses, the effects of a heterozygous Dnmt1 null mutation on the development of immune senescence and autoimmunity were studied (30
). Heterozygous Dnmt1 knockout mice are phenotypically normal but have globally hypomethylated DNA (36
), suggesting that DNA in these mice may become hypomethylated with age and develop signs of immune senescence and autoimmunity more rapidly than their age-matched littermates. Paradoxically, the knockout mice developed age-dependent lymphocytic infiltrates in the liver and salivary glands as well as anti-DNA antibodies more slowly than their littermates. Similarly, the knockout mice developed the memory subset more slowly, maintained IL-2 secretion into old age and increased rather than decreased T cell proliferative responses with age. Comparison of genomic dMC content in lymphocytes confirmed that young knockout mice displayed DNA that was hypomethylated compared with age-matched littermates. Similar studies also confirmed that lymphocyte DNA from the control mice became hypomethylated with age as previously reported (20
,21
). However, genomic dMC content increased with age in the Dnmt1 knockout mice, such that by 18 months of age, genomic dMC content approximated that of 6-month-old littermates. A similar age-dependent increase in DNA methylation was observed in the brains of the knockout mice relative to wild-type littermates. These results indicate that the Dnmt1 null mutation results in a compensatory increase in DNA methylation and prevents the development of autoimmunity and some signs of immune senescence with aging.
To begin to identify a mechanism, transcripts for Dnmt1, Dnmt3a, Dnmt3b and methylcytosine-binding proteins were compared in the brains of young and old Dnmt1 knockout mice and wild-type littermates. The only transcript showing a significant difference between groups was the methylcytosine-binding protein MeCP2; the expression of which was maintained with age in the knockout mice but not in the controls (30
). This makes MeCP2 a candidate for a gene contributing to the response, although studies at the protein level may well indicate additional candidates, and further studies are needed to determine whether sustained MeCP2 expression can prevent age-dependent changes in DNA methylation. However, because MeCP2 is involved in chromatin condensation and gene suppression through interactions with a transcriptional regulator (Sin3A) and histone deacetylases (37
), it is interesting to speculate that sustained MeCP2 expression might prevent age-dependent opening up of chromatin and abnormal expression of genes. How the Dnmt mutation leads to sustained MeCP2 transcript expression is unknown.
The studies summarized above support the concept that age-dependent changes in DNA methylation might contribute to some of the changes in cellular function and gene expression that are associated with aging. Because DNA methylation is intimately involved in determining chromatin structure through proteins such as MeCP2, Sin3A and the histone deacetylases, it is possible that changes in chromatin structure could contribute to alterations of gene expression in aging. Overexpression of silent information regulator 2 (Sir2), a histone deacetylase, has recently been reported to increase the lifespan of Caenorhabditis elegans by up to 50% (38
). It is possible that the overexpression of this enzyme similarly prevents age-dependent opening up of chromatin analogous to sustained MeCP2 expression, and thereby prevents some of the age-dependent changes in gene expression, resulting in increased longevity.
Mechanisms contributing to age-dependent changes in DNA methylation are at present unknown. However, the literature provides examples of endogenous and exogenous mechanisms that modify DNA methylation. A diet deficient in methyl donors can promote reversible hypomethylation of liver DNA (39
–41
). Similarly, folate restriction results in lymphocyte DNA hypomethylation (42
), suggesting that dietary factors might be important. Exogenous agents such as UV light and medications such as procainamide and hydralazine promote DNA hypomethylation (6
,14
). S-Adenosylhomocysteine, an inhibitor of multiple transmethylation reactions including DNA methylation (43
), also increases with age relative to S-adenosylmethionine (44
), which may contribute to the progressive hypomethylation. Several reports indicate that inhibiting signaling through the ERK and JNK pathways can decrease expression of the Dnmt1 gene, leading to DNA hypomethylation (11
,13
). Because chemical inhibitors of these pathways exist (45
), environmental agents with similar properties may modify DNA methylation by this mechanism as well. There also is evidence for endogenous compensatory mechanisms that respond to DNA hypomethylation, including Dnmt1 overexpression in T cells treated with DNA methylation inhibitors and the increase in dMC content observed in the Dnmt1 knockout mice (30
,45
). Alterations in these mechanisms could also participate in changing DNA methylation patterns with aging (30
). Finally, now that de novo methyltransferases and a demethylase have been identified (46
,47
), the possibility of continuous modification of methylation patterns exists. It is likely that additional mechanisms will be identified and that both endogenous and exogenous mechanisms will contribute.
Carcinogenesis
Of all the pathologic consequences of altered DNA methylation, the studies on carcinogenesis are the best established. Mechanisms for which aberrant DNA methylations are implicated in neoplastic transformation include hypomethylation of proto-oncogenes, hypermethylation of tumor suppressor genes, loss of genomic imprinting and chromosomal translocations occurring in hypomethylation regions. Abnormalities in cytosine methylation also contribute to mutations of cytosine to thymidine. The literature on these topics is extensive and is the subject of multiple recent reviews (48
–51
). These topics are further addressed by other authors in this supplement to The Journal of Nutrition, so these concepts will not be further reviewed here, and the reader is referred to these summaries.
Alterations of DNA methylation patterns are now implicated in the pathogenesis of cancer, autoimmunity and some of the cellular functional abnormalities associated with aging. It is likely that additional poorly understood pathologic processes also will be associated with altered gene expression due to changes in DNA methylation patterns. The factors contributing to the changes are incompletely understood but include exposure to UV light and drugs like procainamide and hydralazine, dietary factors and signaling abnormalities. The aging studies performed in the Dnmt1 knockout mice suggest that endogenous factors may contribute as well. It is likely that additional factors will be found to modify DNA methylation patterns. It is hoped that these workshop proceedings prompt studies by others in this interesting, important and developing area.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 This work was supported by U.S. Public Health Service grants AG014783, AR42525 and AI42753, and a Merit grant from the Department of Veterans Affairs.
4 Abbreviations used: 5-azaC, 5-azacytidine; CpG, cytosine guanine dinucleotide; CD11a/CD18, lymphocyte function-associated antigens; dMC, deoxymethylcytosine; Dnmt1, DNA methyltransferase 1; Dnmt3a, DNA methyltransferase 3a; Dnmt3b, DNA methyltransferase 3b; ERK, extracellular signal-regulated kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IGF2, insulin-like growth factor 2; IL-2, interleukin-2; JNK, c-jun NH2-terminal kinase; LFA-1, lymphocyte function-associated antigen-1; MeCP2, methyl-CpG-binding protein 2; MEK, mitogen-activated protein/extracellular signal-regulated kinase; MHC, major histocompatibility complex; RLGS, restriction landmark genome scanning; Sir2, silent information regulator; UV, ultraviolet.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONLITERATURE CITED |
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 S. Garaud, C. Le Dantec, C. Berthou, P. M. Lydyard, P. Youinou, and Y. Renaudineau Selection of the Alternative Exon 1 from the cd5 Gene Down-Regulates Membrane Level of the Protein in B Lymphocytes J. Immunol., August 1, 2008; 181(3): 2010 - 2018. [Abstract] [Full Text] [PDF]
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Q. Lu, A. Wu, and B. C. Richardson Demethylation of the Same Promoter Sequence Increases CD70 Expression in Lupus T Cells and T Cells Treated with Lupus-Inducing Drugs J. Immunol., May 15, 2005; 174(10): 6212 - 6219. [Abstract] [Full Text] [PDF]
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 C. G. Kevil, M. J. Hicks, X. He, J. Zhang, C. M. Ballantyne, C. Raman, T. R. Schoeb, and D. C. Bullard Loss of LFA-1, but not Mac-1, Protects MRL/MpJ-Faslpr Mice from Autoimmune Disease Am. J. Pathol., August 1, 2004; 165(2): 609 - 616. [Abstract] [Full Text] [PDF]
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 N. K. Fukagawa and R. A. Galbraith Advancing Age and Other Factors Influencing the Balance between Amino Acid Requirements and Toxicity J. Nutr., June 1, 2004; 134(6): 1569S - 1574S. [Abstract] [Full Text] [PDF]
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