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Biochemical Society Transactions (2004) Volume 32, part 6
Folate and DNA methylation during in utero
development and aging
J.A. McKay*1 , E.A. Williams† and J.C. Mathers*
*Human Nutrition Research Centre, School of Clinical Medical Sciences, University of Newcastle upon Tyne, NE1 7RU, U.K., and †Human Nutrition Unit,
University of Sheffield, Northern General Hospital, Sheffield S5 7AU, U.K.
Abstract
DNA methylation is one of several epigenetic mechanisms that play a regulatory role in genome
programming and imprinting during embryogenesis. Aberrant DNA methylation has been implicated in
the pathogenesis of a number of diseases associated with aging, including cancer and cardiovascular and
neurological diseases. Evidence is accumulating that dietary factors in utero modulate disease risk in later
life. Although folic acid is a key component of DNA methylation, the impact of folic acid availability in utero
on DNA methylation patterns and disease risk in adulthood is at present poorly characterized. This review
describes the relationship between folic acid and DNA methylation, and the association between DNA
methylation during in utero development and aging.
Introduction
Nutritional insults during foetal and neonatal development
are hypothesized to have a detrimental impact on adult
morbidity and mortality [1], but the underlying mechanisms
are poorly understood. Folate insufficiency in pregnancy
is well recognized as a risk factor for NTDs (neural tube
defects), but may also influence NCD (non-communicable
disease) risk in later life by the critical role of folate in DNA
methylation and synthesis of purines and pyrimidines. This
review focuses on the interaction between folate and DNA
methylation during in utero development and aging.
DNA methylation
DNA methylation is the addition of a methyl group to a
cytosine residue present in a CpG dinucleotide [2]. CpG
dinucleotides occur at low abundance throughout the human
DNA genome and tend to concentrate in regions known as
CpG islands found in the promoter regions of genes. A CpG
island is a region of DNA with more than 200 bp, a high G-C
content and an observed/expected ratio of CpGs greater
than 0.6 [2]. CpG dinucleotides are typically methylated
in non-promotor regions and unmethylated in promoter
regions. Methylation within the promoter region correlates
with transcriptional silencing and the methylation status of
CpG islands is believed to regulate gene transcription through
the inhibition of transcription factor binding either directly or
via altered histone acetylation [3]. This regulatory function is
consistent with the role DNA methylation plays in silencing
genes on the inactive X chromosome, in imprinted genes and
parasitic DNA [2].
Key words: aging, cancer, DNA methylation, folate, in utero development.
Abbreviations used: NCD, non-communicable disease risk; NTD, neural tube defect.
1
To whom correspondence should be addressed (email [email protected]).
C 2004
Biochemical Society
Changes in DNA methylation through
in utero development and aging
DNA methylation is critical to mammalian development.
Methylation patterns are established during embryogenesis
and remain largely unchanged in adult cells [4]. Genomewide demethylation occurs before embryo implantation followed by de novo global remethylation after implantation
in advance of organ development, allowing gene-specific
methylation patterns to develop, which determine tissuespecific transcription [5]. DNA methylation is also involved
in the repression of either the maternal or paternal
allele of imprinted genes. Incorrect development of DNA
methylation patterns can lead to embryonic lethality [6] and
developmental malformations [7].
Although methylation patterns are established during
early life, these are not fixed. Gradual hypomethylation
of the vertebrate genome occurs with age in most tissues
(reviewed in [8]) accompanied by aberrant hypermethylation
in the promoter regions of genes, e.g. ER, IGF2 and cmyc (reviewed in [8]). Such age-related methylation has been
implicated as an early step in carcinogenesis [9]. Therefore,
not only is it vital that DNA methylation patterns develop
correctly during early life, but the preservation of these
patterns may be beneficial to long-term health.
Folate, DNA methylation and
in utero development
Folate, a water-soluble vitamin B, is essential for the transfer of one-carbon units [10]. It is indispensable in the
methionine cycle and, therefore, for the synthesis of Sadenosylmethionine, the common methyl donor for DNA
methylation. Folate deficiency leads to a decrease in S-adenosylmethionine and an increase in homocysteine. Dietary
deficiencies in folate have been observed to decrease genomewide methylation both in humans and in animal models, and
Energy: Generation and Information
methylation is corrected when a folate-replete diet is restored
(reviewed in [11]).
The importance of folate in pregnancy for the prevention
of NTDs has been well documented [10] and is further
demonstrated in the Folbp1 (folate-binding protein 1)
knockout mouse. Matings of heterozygous parents produced
only Folbp+/− and Folbp+/+ offspring, indicating that
complete inactivation of the gene required for cellular uptake
of folate was embryo-lethal [12].
The agouti mouse model provides a more subtle demonstration of the importance of methyl donors, including folate,
in DNA methylation and embryonic development [13].
Methyl donor supplementation of agouti dams during pregnancy causes the agouti gene to be silenced by methylation,
altering the coat colour of the offspring. The present study
suggests that maternal diet can have a significant effect on
DNA methylation of the offspring.
Folate, DNA methylation and NCD risk
There are several genetic and acquired NCDs associated
with abnormal DNA methylation (reviewed in [10]). Prader–
Willi, Angelman’s and Beckwith–Wiedemann syndromes all
result from abnormal demethylation of the silenced allele of
imprinted genes causing biallelic expression. Abnormalities
in folate metabolism and DNA methylation have been
associated with Down’s syndrome, and aberrant DNA
methylation has been implicated in the pathogenesis of
neurological disorders including Alzheimer’s, Parkinson’s
and Huntington’s diseases [14]. Altered DNA methylation
has been extensively documented in tumorigenesis [10].
Genome-wide hypomethylation is associated with malignancy, which may cause chromosomal translocations and may
lead to genetic mutations via cytosine to thymine transitions.
Aberrant promoter region methylation, accompanied by
altered gene expression for several proto-oncogenes and
tumour suppressor genes, has been observed in a range of
cancers and is probably an early event in carcinogenesis.
Future studies will provide insight into how folate supply
during development affects methylation status and chronic
disease risk in later life.
Implications for public health
The roles played by folate in nucleotide synthesis and in
methylation of cell macromolecules explain the vital role of
this vitamin during development in utero. Folate supplements
in early pregnancy reduce the risk of NTDs and, possibly,
other birth defects. Aberrant methylation patterns appear to
be important components of the aetiology of cancers [10] and
cardiovascular and neurological diseases.
This result suggests that extra folate may be beneficial;
however, since excess folate may mask the early symptoms
of vitamin B12 deficiency, the risk/benefit ratio for food
fortification by folate remains uncertain.
J.A.M. holds a BBSRC studentship.
References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Barker, D.J.P. (1997) Nutrition 13, 807–813
Jones, P.A. and Takai, D. (2001) Science 293, 1068–1070
Geiman, T.M. and Robertson, K.D. (2002) J. Cell. Biochem. 87, 117–125
Finnell, R.H., Spiegelstein, O., Wlodarczyk, B., Triplett, A., Pogribny, I.P.,
Melnyk, S. and James, J.S. (2002) J. Nutr. 132, 2457S–2461S
Razin, A. and Shemer, R. (1995) Hum. Mol. Genet. 4, 1751–1755
Li, E., Bestor, T.H. and Jaenisch, R. (1992) Cell (Cambridge, Mass.) 69,
915–926
Matsuda, M. and Yasutomi, M. (1992) Anat. Embryol. 185, 217–223
Richardson, B. (2003) Aging Res. Rev. 2, 245–261
Yuasa, Y. (2002) Mech. Ageing Dev. 123, 1649–1654
Lucock, M. (2000) Mol. Genet. Metab. 71, 121–138
Choi, S.-W. and Mason, J.B. (2002) J. Nutr. 132, 2413S–2418S
Piedrahita, J.A., Oetama, B., Bennet, G.D., van Waes, J., Kamen, B.A.,
Richardson, J., Lacey, S.W., Anderson, R.G. and Finnell, R.H. (1999)
Nat. Genet. 23, 228–232
Waterland, R.A. and Jirtle, R.L. (2003) Mol. Cell. Biol. 23, 5293–5300
Mattson, M.A. (2003) Aging Res. Rev. 2, 329–342
Received 22 July 2004
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Biochemical Society
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