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3
*
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 and Divisions of
Molecular Epidemiology and
**
Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079
3To whom correspondence should be addressed. E-mail: cooneycraiga{at}uams.edu.
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ABSTRACT |
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 TOP ABSTRACT Epigenetic variation in...DNA methylation and epigeneticsMethyl metabolism and 5-MCThe yellow agouti mouse:...METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • diet • methylation • epigenetic • maternal • supplement
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Epigenetic variation in populations |
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TOPABSTRACTEpigenetic variation in...DNA methylation and epigeneticsMethyl metabolism and 5-MCThe yellow agouti mouse:...METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). In these studies, considerable credible efforts were made to assure that animals received the same food and were maintained at the same temperature, humidity, light and dark cycle, etc. (1
–5
). Although there may have been some variations in the amount of food eaten, experiments to control this variable still yield a considerable spread in longevity (1
–5
).
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), fox (7
) and rat (8
). Epigenetic variations established in development and affecting health and survival have already been demonstrated in mice and rats (6
,8
,9
). Even though epigenetic variation is a likely key factor in mammalian health and life span variance, it remains uncontrolled and unaccounted for in most populations. As with other traits, it seems likely that epigenetically determined ones vary across a range (Fig. 1)
, even though they rarely present themselves in ways that are readily observed and quantified. Epigenetic and environmental interactions can be studied with minimal confounding genetic and environmental variation by using well-characterized inbred mice. |
DNA methylation and epigenetics |
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TOPABSTRACTEpigenetic variation in...DNA methylation and epigeneticsMethyl metabolism and 5-MCThe yellow agouti mouse:...METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–12
); inactivation of X chromosomes (13
,14
); and silencing of some, possibly many, genes including many showing genomic imprinting and epigenetic inheritance (12
,15
–19
). ERVs contain viral genes and promoter enhancer sequences [long terminal repeats (LTRs)] and can express their viral genes as well as drive expression of nearby housekeeping or tissue-specific genes (6
,10
–12
). 5-MC is the best-characterized epigenetic mechanism in mammals, and both DNA methyltransferase (Dnmt)1 and one of the chromatin proteins that bind methylated DNA [methyl-cytosine guanine dinucleotide (CpG)-binding protein 2 (MeCP2)] are necessary for mammalian development (20
,21
). Inheritance of 5-MC patterns, by dividing cells in vivo or in vitro, can occur with imperfect fidelity. The mechanism appears to hinge on a marked (10- to 20-fold) substrate preference of the maintenance methylase for hemimethylated DNA. Thus, at the DNA replication fork, the semiconservatively synthesized daughter duplexes are preferentially converted to fully methylated status, duplicating the parental pattern (22
–25
). Inheritance of 5-MC patterns from the maternal or paternal germline to the offspring has been demonstrated in numerous cases of imprinting (16
,26
–29
). In some cases of epigenetic inheritance, inheritance of specific somatic 5-MC patterns from one generation of animals to the next has been demonstrated (17
,18
,30
). |
Methyl metabolism and 5-MC |
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TOPABSTRACTEpigenetic variation in...DNA methylation and epigeneticsMethyl metabolism and 5-MCThe yellow agouti mouse:...METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,32
) (Fig. 2
). Dnmts use S-adenosylmethionine (SAM) as a donor to methylate cytosines in DNA. At least some Dnmts are inhibited by the reaction product S-adenosylhomocysteine (SAH), and some or all are zinc-finger enzymes (24
,33
–35
).
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,36
–38
).
Mammals and other animals have been selected for efficient youthful reproduction and not for extended longevity (31
). There is no a priori reason for thinking that nutritional requirements adequate for growth and reproduction are optimal for long-term health and longevity. Likewise, maternal nutrition adequate for producing offspring with normal growth and reproduction is not necessarily the optimal balance for offspring’s long-term health and longevity.
To address questions of optimal nutritional balance, it is necessary to study supplementation as well as deficiency. Few studies address the role of methyl supplementation in DNA methylation or in determination of epigenetic phenotype (6
).
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The yellow agouti mouse: epigenetics linked to coat color |
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TOPABSTRACTEpigenetic variation in...DNA methylation and epigeneticsMethyl metabolism and 5-MCThe yellow agouti mouse:...METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) and 5-MC (18
), this Avy gene is expressed to different degrees in genetically identical mice. Failure to epigenetically suppress the Avy gene during development causes the agouti gene to be ectopically overexpressed later in life. This high level of agouti expression in essentially all tissues causes numerous downstream metabolic and endocrine effects that ultimately affect gross biological end points such as obesity and survival. This agouti overexpression and its physiological effects have been termed the yellow agouti obese mouse syndrome. This syndrome includes a yellow or mottled yellow coat color, altered metabolism and obesity from a young age. It also results in adult diabetes, increased cancer susceptibility and, by 24 mo of age, twice the mortality seen in normal mice (6
,39
).
In mice carrying the Avy allele, a continuous spectrum of variegated coat color patterns of agouti areas (eumelanic mottling) on a yellow background characterizes the majority of Avy/a mice. Their phenotypes are defined by the degree of this mottling. Thus a Y5 "clear yellow" mouse (Fig. 3a
) is not mottled and is at one extreme of this spectrum, whereas the Y0 pseudoagouti mouse (Fig. 3
b) has essentially normal (agouti) hair and occupies the other extreme of the spectrum. The Y0 phenotype resembles the species-type "agouti" (Aw/-) phenotype with essentially normal agouti coat color pattern. Y0 mice do not become obese or diabetic and, in comparison with Y2-Y5 mice, are relatively resistant to liver tumorigenesis (9
).
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Coat color and other characteristics of Avy/a mice are determined by the level and tissue specificity of agouti gene expression. In animals with a partial or full yellow coat, agouti is overexpressed both ectopically and in the hair follicles. An agouti coat indicates cyclic expression of agouti limited to the hair follicles (Fig. 4
).
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,40
), much less used maternal treatments to affect this variation (6
). Here we describe how maternal diet affects the distribution of epigenetically determined phenotypes and DNA methylation in offspring. |
METHODS |
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TOPABSTRACTEpigenetic variation in...DNA methylation and epigeneticsMethyl metabolism and 5-MCThe yellow agouti mouse:...METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Restriction enzymes (HaeII and HinP1I) were from New England Biolabs (Beverly, MA). DNAzol was from the Molecular Research Center (Cincinnati, OH). Taq polymerase (Amplitaq) and various polymerase chain reaction (PCR) reagents were from PE Applied Biosystems (Foster City, CA). All other chemicals were of analytical grade or molecular biology grade.
Animals and epigenetic phenotypes
All animal experiments were approved by and conducted in accordance with the Animal Care and Use Committee of the National Center for Toxicological Research. Animals were housed and bred as described previously (6
). Two inbred mouse strains that carry both the a and Avy mutant alleles at the agouti locus (41
) were used. These strains, VY/WffC3Hf/Nctr-Avy (VY) and YS/WffC3Hf/Nctr-Avy (YS) have been described previously (39
). The a and Avy mutant alleles are of great utility because the level and pattern of agouti gene expression can be determined from each animal’s coat color pattern (6
) as illustrated in Figure 3
. The a allele is virtually null, leaving expression of agouti and determination of coat color in Avy/a mice to the single copy of the Avy allele.
Ectopic agouti gene expression produces the yellow agouti obese mouse syndrome. The associated coat color is visually apparent just 7 d after birth (6
,41
). Offspring were produced by a/a x Avy/a matings and the degree of mottling (Y0–Y5) of their coats was visually estimated. The estimated ranges of coat color patterns for the degrees of mottling are as follows: Y0, no yellow, 100% agouti; Y1, <5% yellow, >95% agouti; Y2, 5–33% yellow, 67–95% agouti; Y3, >33–67% yellow, <33–67% agouti; Y4, 67–99% yellow, 1–33% agouti; Y5, >99% yellow, <1% agouti. Y1 mice specifically have a few thin yellow lines or tiny yellow spots, mainly in the rump area, on a Y0 background (6
) (Fig. 3
b).
Maternal diet studies
Dams of the inbred mouse strains VY and YS were fed diets with methyl supplementation at two different levels during pregnancy as described previously (6
). Methyl-supplemented diets were designed to provide substantially increased amounts of cofactors and methyl donors for methyl metabolism (31
) and Dnmt (24
,34
,35
). Methyl-supplemented diets were prepared by fortifying the control "methyl-sufficient" NIH-31 diet (6
). All diets were pelleted after addition of the supplements and fed ad libitum. Three levels of diet were used: control (NIH-31), mid-range methyl supplemented (MS) and high level methyl supplemented including supplemental zinc and methionine (3SZM) (6
) (Table 1
).
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). Animals were euthanized by carbon dioxide asphyxiation and their tissues were frozen for subsequent analysis. Animals at the phenotypic extremes (including Y1, which was exclusive to the 3SZM diet group) were assayed for DNA methylation of the Avy allele proximal LTR. DNA preparation
DNA was isolated from tissues using DNAzol (Molecular Research Center) (42
). Tissue (e.g., liver or kidney) was homogenized in DNAzol and put through a series of centrifugations, ethanol precipitation and washes according to the DNAzol protocol with slight modifications. The main modifications were that tissues were often left to dissolve in DNAzol for 1 d or more after homogenization and, at the end of the procedure, DNA was dissolved and stored in Tris-EDTA buffer [TE; 10 mM Tris-HCl, 0.1 mM ethylenediaminetetraacetic acid (EDTA), pH 7.4]. After full dissolution, a small aliquot of each DNA was diluted 50-fold with TE, and the ultraviolet spectrum was determined for subsequent calculation of DNA concentration.
PCR and DNA sequencing
A set of DNA primers for PCR was designed to span a region including the Avy IAP-LTR proximal to the agouti gene. One of these primer sequences (5'-GAGTTTAGCACATACCTTCT-3') lies in an agouti exon (43
), and the other (5'-AATTTTCAGCCCTATCTTAA-3') was designed to match an established IAP sequence (44
). PCR conditions were 94°C for 60 s; 30 cycles of 94°C for 30 s, 56°C for 30 s and 69°C for 30 s; then 72°C for 10 min and 4°C indefinitely. A "hot start" procedure was used in which the polymerase (with some buffer) was separated from the other components by a wax layer that melts at 80°C (AmpliWax PCR gems; PE Applied Biosystems). A PCR product of 870 base pairs (bp) was identified by agarose gel electrophoresis and recovered using a QIAquick Gel Extraction Kit (Qiagen, Valencia, CA). This product was sequenced in both directions with the aid of the above two primers at the University of Arkansas for Medical Sciences (UAMS) Sequencing Facility using a Model 377 DNA Sequencer and Big Dye terminator chemistry (PE Applied Biosystems).
DNA methylation
Sites in the LTR containing CpGs were used as targets to assay DNA methylation. One HaeII site (PuGCGCPy) and three HinP1I sites (GCGC) are found in the LTR. An additional HinP1I site is found just outside the LTR but within the IAP sequence. Both HaeII and HinP1I are methyl-sensitive restriction enzymes; i.e., they will not cut DNA if the sequence is PuGMCGCPy or GMCGC, respectively. Note that all HaeII sites are also HinP1I sites but not conversely.
LTR methylation in Avy/a mice was determined by cutting DNA with either HaeII or HinP1I, heat inactivating the enzyme (95°C for 20 min) and amplifying the resulting DNA using PCR. A control was run in which half the sample was set aside before restriction digestion and water was added in place of restriction enzyme. In this control, no diminution of PCR amplification will take place as a result of unmethylated (cleaved) sites in the DNA. In the restriction-digested samples, PCR amplification is attenuated as a result of cleavage at unmethylated sites in the Avy IAP-LTR sequence.
The PCR products from the control and restricted DNA samples were run side by side on an agarose gel, which was then stained with ethidium bromide, viewed under ultraviolet light and digitally photographed. This provided a permanent record of the pattern and intensity of the DNA bands. These digital images were then quantified using NIH Image software. These general methods of DNA isolation, restriction digestion, PCR and gel analysis and quantification have been described previously for other systems (45
).
Statistical analysis
Comparisons of DNA methylation levels based on the extent of target PCR amplification were done using Student’s t test [Microsoft Excel (Microsoft, Redmond, WA) or Microcal Origin (OriginLab, Northampton, MA) software] for comparison of group means and by Spearman rank-order correlation (Microcal Origin software) for measures of individuals. Differences were considered significant when P < 0.05. Comparisons of groups for their epigenetic phenotypes were analyzed as described previously (6
).
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RESULTS |
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TOPABSTRACTEpigenetic variation in...DNA methylation and epigeneticsMethyl metabolism and 5-MCThe yellow agouti mouse:...METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Animals born to dams fed different maternal diets were evaluated for epigenetic phenotype, according to the degree of agouti in their coats, using the criteria described above and previously (6
). Distributions are plotted in Figure 5
. These histograms indicate a broad distribution of epigenetic variation in these populations of mice. There is a shift in distribution toward phenotypes with more agouti coat (combined black and yellow pigment in the hair) as increasing levels of methyl supplement are added to the diet. These trends toward agouti phenotype with increasing maternal methyl supplement are highly significant [P < 0.001 for VY strain and P < 0.05 for YS strain (6
)].
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The contiguous sequence for this region of the Avy gene was determined and found to contain the expected IAP-LTR and agouti sequences (Fig. 6
). The homology to agouti (46
) is 100% and the homology to IAP-LTRs is also very high (97–100% identity match with several other known IAP-LTRs in GenBank; e.g., Ref. 44
and GenBank accession no. M99279). Figure 6
also shows a schematic diagram of the DNA and restriction sites used.
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); scans of the lanes of this gel are presented in Figure 7
b. In each case, the restriction enzyme-digested DNAs from Y0 and Y1 mice give a strong band after PCR with intensity 
58% of that produced after PCR uncleaved controls (Figs. 7
and 8
). This indicates a high level of methylation on the HaeII site and/or all four of the HinP1I sites in the LTR. In contrast, restriction-digested DNAs from Y4 and Y5 yellow mice produced <15% of the control signal (Figs. 7
and 8)
, indicating low methylation on the HaeII site and/or at least one of the four HinP1I sites in the LTR. These levels have been quantified from numerous gels, and some of these results are presented in Figure 8
. The methylation levels of agouti proximal-LTR HaeII sites of the least yellow phenotypes (Y1 and Y0) average 79% of controls (n = 8) while those of the most yellow phenotypes (Y5 and Y4) average only 11% of controls (n = 4); the difference is significant at P < 0.000001. Additional qualitative HaeII digest data and quantitative HinP1I digest data are fully consistent with these results. The Spearman rank-order correlation coefficient (rS) for a regression of methylation extent (the percentage of intact band) against yellow pigmentation (Y class) is 0.979, with P < 0.03 (Fig. 8)
. This correlation coefficient represents a subset of data based only on the two least yellow (Y0 and Y1) and the two most yellow (Y4 and Y5) phenotypes.
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DISCUSSION |
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TOPABSTRACTEpigenetic variation in...DNA methylation and epigeneticsMethyl metabolism and 5-MCThe yellow agouti mouse:...METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
Epigenetic variation, a likely key factor in health and life span variance, remains an uninvestigated factor in most studies of health and longevity. Just as natural populations exhibit distributions of trait values, diets and lifestyles, it seems likely that epigenetically determined traits vary across a broad range as well; however, they may only rarely present themselves in ways that we can readily observe or quantify in populations.
Epigenetic variation affecting health and life span could contribute significantly to individual variation in longevity, as seems to be the case in experimental animals with identical genetic and environmental backgrounds. Similarly, epigenetic variation could account for a significant portion of the health and life span variation seen in humans, although parsing these influences from other variables in humans would be a daunting task without guidance from well-defined examples in animal systems. The epigenetic variations that affect adult health and life span are probably established during embryonic and fetal development (Fig. 9
). Many likely involve the incomplete methylation of genes and ERVs. Using well-characterized inbred mice, epigenetic and environmental interactions can be studied with a minimum of confounding genetic and environmental variation.
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,43
,47
). Some intermediary steps have been identified between agouti overexpression and long-term adverse health effects in yellow mice (39
,47
). Furthermore, many of these effects bear similarities to the effects of agouti homologues in humans (47
). Shifting the distribution of epigenetic variation
We show a shift in the distribution of epigenetic variation in offspring after maternal methyl supplementation. Although a substantial range of variation remains in these offspring, the ability to shift the distribution of epigenetic variation raises the possibility that the distribution of health variation in populations could be shifted and, on balance, improved. Further treatments, or cumulative multigenerational treatments, might further shift the distribution of epigenetic phenotypes. From a health perspective this might greatly improve the health and longevity of the population.
One useful display of epigenetic variation would be the level and distribution of methyl groups on specific functional sequences such as LTRs associated with cellular or viral genes. This may not have a 100% correspondence with phenotype or gene expression because a preponderance of methylation is in many cases sufficient to suppress expression (48
). Thus, some variation could exist in DNA methylation that would nevertheless result in apparent homogeneity in gene expression or overt phenotype. As identification of human sequences involved in epigenetic variation increases, it may be possible to determine epigenetic phenotype and even predict disease susceptibility by measuring DNA methylation of specific sequences.
Many human diseases may have significant epigenetic components. Epigenetics plays an important role in many cancers that appear late in life (49
) and may have roots in epigenetic inheritance or epigenetic variation established in early development. Rare conditions such as Prader-Willi and Angelman syndromes have significant inherited or developmental epigenetic components (50
). Likewise, some childhood cancers (51
) and much more common diseases such as diabetes (52
) and some psychiatric disorders (53
) may have significant inherited or developmental epigenetic components. The tendency of diabetes and some psychiatric disorders to defy purely genetic characterization further suggests a significant epigenetic (or other environmentally influenced) component (53
).
DNA methylation variation in mammals
Insufficient methylation of many parts of the genome can lead to disease in humans (54
–56
), and, in mice, lowered survival (6
). Although some levels of 5-MC have been deemed insufficient for particular purposes, there is little information available concerning optimal levels of 5-MC. It might be assumed that as yet to be defined "normal" levels of 5-MC are "adequate"; however, there are few studies that address whether increased levels of 5-MC on particular sequences might be protective against disease or might extend life span beyond normalcy. It has long been known that DNA methylation declines with age in mice (31
,57
–59
). It has been recently shown that expression of the MeCP2 gene drops substantially with age in mice (60
). It has been proposed for some time that higher densities of DNA methylation on certain sequences allow for greater surety of health (10
,12
) and greater life span (31
,61
).
Numerous nutritional and biochemical studies (37
,38
,62
) as well as epidemiological studies (63
) have shown that nutrients for methyl metabolism are essential for maintaining DNA methylation and preventing cancer in rodents and humans. However, few studies have addressed optimal levels and combinations of nutrients with respect to "normal" levels of 5-MC, and fewer still address nutrient levels and combinations for "optimized" 5-MC. The present study provides one practical means to manipulate 5-MC and determine the effects on the health and life span of offspring. Because mice and humans share the same basic mechanisms for methylation of DNA and gene regulation, the application of such findings in mice could lead to improved maternal nutritional balances to improve the health and life span of humans.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by National Center for Toxicological Research Project 6964 (to G.L.W.) and by the Oak Ridge Institute for Science and Education (to C.A.C.). Work in this laboratory on nutritional supplements, epigenetics and DNA methylation is supported by a grant from Life Extension Foundation (to C.A.C.).
4 Abbreviations used: 3SZM, high level methyl supplemented including zinc and methionine; 5-MC, 5-methyldeoxycytidine; A, adenine; bp, base pair; C, cytosine; CpG, cytosine guanine dinucleotide; Dnmt, DNA methyltransferase; EDTA, ethylenediaminetetraacetic acid; ERV, endogenous retrovirus; G, guanine; GCGC, guanine/cytosine/guanine/cytosine; IAP, intracisternal A particle; LTR, long terminal repeat; MeCP2, methyl-CpG-binding protein 2; MS, mid-range methyl supplement; PCR, polymerase chain reaction; rS, Spearman rank-order correlation coefficient; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; TE, Tris-EDTA buffer; UAMS, University of Arkansas for Medical Sciences; VY, mouse strain VY/WffC3Hf/Nctr-Avy; YS, mouse strain YS/WffC3Hf/Nctr-Avy.
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LITERATURE CITED |
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TOPABSTRACTEpigenetic variation in...DNA methylation and epigeneticsMethyl metabolism and 5-MCThe yellow agouti mouse:...METHODSRESULTSDISCUSSIONLITERATURE CITED |
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