Epigenetics in congenital diseases and pervasive developmental disorders
Environ Health Prev Med
Epigenetics in congenital diseases and pervasive developmental disorders
Takeo Kubota 0
0 T. Kubota (&) Department of Epigenetics Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi , 1110 Shimokato, Chuo, Yamanashi 409-3898 , Japan
Epigenetics is an intrinsic mechanism that alters gene function - not by altering DNA sequences, but by chemically modifying the DNA and chromosomal histone proteins. Epigenetics is involved in genomic imprinting and X-chromosome inactivation in humans, and the failure of this mechanism causes a subset of congenital syndromes and cancers. Until recently, it has been believed that epigenetic modification is stable and that the pattern is faithfully preserved following DNA replication during cell division, leading to stable epigenomic patterns during one's life-time. However, more recent reports of environmental stress altering the epigenomic patterns within a short time frame after birth, followed by alterations in gene expression and phenotype, indicate that epigenetics is not only involved in congenital neurodevelopmental diseases but also in acquired diseases, including pervasive developmental disorders, through gene-environmental interaction. In this review, I introduce the subject of congenital diseases with abnormalities in known epigenetic mechanisms and discuss possible epigenetic abnormalities in pervasive developmental disorders.
Autism DNA methylation Environment
Pervasive developmental disorders
It is a well-established paradigm that most diseases are
caused by both genetic and environmental factors.
Numerous studies presented at the annual meeting of the Japanese
Society for Hygiene showed that environmental factors
which can damage DNA strands are associated with
carcinogenesis. However, the mechanism that operates between
the genes and the environmental factors still remains to be
elucidated in detail. Several lines of more recently published
evidence suggest that the epigenetic mechanism, which
alters gene function, can be affected by environmental
factors. This in turn provides us a new insight – that a gene–
environmental interaction via epigenetic mechanism may be
associated with neurodevelopmental and mental diseases.
Social environmental factors are known to contribute to
the development of character in childhood and the
occurrence of depression. However, autism has recently been
recognized as a disease not caused by environmental
factors (e.g., maternal care), but by genetic factors, suggesting
that the autistic condition is determined before birth.
Weaver et al. [
] reported that DNA methylation status can
be altered by mental stress shortly after birth, which in turn
affects gene function in brains related to mental stress. It
has also been reported that a frequent use of an
antidepressant normalizes epigenetic function of a gene in the
] and that epigenomic information can be different
between monozygotic twins who share identical genomic
]. These findings suggest that pervasive
developmental disorders and mental diseases may be
caused by environmental factors after birth through an
Epigenetics is an intrinsic mechanism that alters gene
function by chemically modifying DNA and chromosome
histone proteins without altering the DNA sequence. When
DNA is modified with a methyl (CH3) residue in the CpG
islands [cytosine followed by guanine (CpG)-rich regions]
in the gene promoters, genes are usually turned off. A
recent issue in Nature introduced epigenetic to the readers
using an example: ‘‘If the DNA sequence of the genome is
like the musical score of a symphony, then the epigenome
is like the key signatures, phrasing and dynamics that show
how the notes of the melody should be played’’ [
maintain a healthy condition, we need not only the
appropriate genetic factors but also the appropriate
In this review, I introduce well-established congenital
diseases in which epigenetic disorders are involved. I then
discuss perspective aspects in pervasive developmental
disorders which may be caused by environmental factors
via the epigenetic mechanism.
Congenital diseases associated with genomic imprinting
Genomic imprinting is one of the first examples of an
epigenetic phenomenon discovered in humans. One of two
parental alleles is inactivated epigenetically in imprinted
genes, whereas both of the two parental alleles are active in
most of the genes. One such imprinted gene is the SNRPN
gene, located in chromosome 15q12; in this case, the
maternal allele is inactivated and the paternal allele is
expressed. The UBE3A gene is another imprinted gene,
located in the same chromosomal region as SNRPN, but with
the opposite imprinting (the paternal allele is inactivated; the
maternal allele is expressed). Failure of expression of the
former gene due to deletion of paternal chromosome 15 or
abnormal methylation of the paternal allele results in
Prader–Willi syndrome, which is a neurodevelopmental disease
characterized by severe obesity. Failure of expression of the
latter gene due to either deletion of maternal chromosome 15
or abnormal methylation of the maternal allele results in
Angelman syndrome, a distinct neurodevelopmental disease
that is characterized by severe epileptic seizures (Fig. 1a) [
]. To date, nearly 100 imprinted genes have been identified.
Imprinted genes are not distributed evenly throughout the
human genome; instead they are clustered in certain
genomic regions. Not only deletion (described above) but also
duplication of the 15q12 region causes an autistic disease
, indicating that the brain is an organ in which gene
expression should be strictly regulated.
Congenital diseases associated with X-chromosome inactivation
The sex chromosomes are different in males and females
(XY in males; XX in females). The X-chromosome has a
A Defect in genomic imprinting
B Defect in X-chromosome inactivation
C Defect in DNA methylation
D Defect in methylated DNA-binding protein
Fig. 1 Epigenetic disorders found in congenital diseases. a Genomic
imprinting is referred to as mono-allelic expression depending on
parental origin. The inactivated allele is methylated in its promoter
region (filled circle), whereas the expressing allele is not methylated.
In some pediatric diseases, both alleles are methylated, resulting in a
complete lack of gene expression. b One of two X-chromosomes are
normally inactivated in females. In some rare pediatric diseases, both
X-chromosomes are active, resulting in severe mental retardation.
c DNA is methylated by specific enzymes, such as DNA
methyltransferases (DNMTs). In a disease with immunodeficiency
[immunodeficiency, centromere instability (ICF) syndrome], mutant
DNMT3B fails to methylate DNA in certain genomic regions.
d Genes are suppressed by epigenetic mechanism via certain proteins,
such as methyl-CpG (cytosine followed by guanine-rich areas)
binding proteins. In one autistic disease, denoted as Rett syndrome,
mutant methyl-CpG binding protein 2 (MeCP2) fails to suppress its
number of genes, whereas the Y-chromosome has only a
few, indicating that females have more genes than males.
To compensate for ‘‘the genetic discrimination’’ between
females and males, one of the two X chromosomes in
females is inactivated. The inactivated chromosome is
randomly chosen between the paternally derived X and the
maternally derived X in each cell during early development
(Fig. 1b) [
]. If X inactivation does not occur during early
development properly, the female fetus cannot be born.
Clone animal experiments have proven this hypothesis:
most cloned animals produced by somatic nuclear transfer
are aborted in the middle of the fetal period, and many of
such aborted cloned animals have shown failure of
]. Thus, the establishment of the
appropriate methodology to achieve normal X-inactivation is one
of important conditions of successful somatic cloning .
Females can be born when one of X chromosomes is
very small, even if X-inactivation does not work properly
and, consequently, both X chromosomes are active.
However, such females usually have severe mental and
developmental retardation, suggesting that over-expression
of the X-linked genes within the tiny X region has a very
large effect (Fig. 1b) [
Congenital diseases associated with defects in the epigenetic mechanism
Recent advances in our understanding of epigenetics has
resulted in the identification of many of the proteins
involved in epigenetic gene regulation, including enzymes
that transfer methyl (CH3)-residues onto DNA strands (the
so-called methylases). Mutations of one particular
methylase, DNMT3B, lead to a congenital immunodeficiency
disease, immunodeficiency, centromere instability (ICF)
syndrome. Patients with this syndrome are characterized by
Immunodeficiency, centromere instability, and facial
abnormalities. It has been demonstrated that the
chromosome centromere instability (breakage near centromeric
regions in chromosomes 1, 9, and 16 at the step of
preparation of chromosome slides) is caused by a lack of proper
methylation in heterochromatin due to a deficiency of this
]. However, the pathogenesis of
immunodeficiency and facial abnormalities is not known,
although over-expression of certain causative genes due to
hypomethylation is assumed (Fig. 1c).
Methyl-CpG binding proteins (MBDs) are also
epigenetic-contributing proteins. Mutations of one such MBD
(MeCP2) cause an X-linked neurodevelopmental disorder
(Rett syndrome) that is characterized by autism, epilepsy,
and a specific hand movement (hand wrapping) [
Patients with Rett syndrome are all females, since males
with MeCP2 mutations are embryonic lethal (X-linked
dominant traits). MeCP2 protein is bound to the regulatory
regions of genes and suppresses gene expression. Thus, the
pathogenesis of Rett syndrome is thought to be
dysregulation of MeCP2-target genes in the brain (Fig. 1d). Some
of these genes have recently been identified, including the
BDNF gene [
Pervasive developmental disorders potentially associated with defects in the epigenetic mechanism
Abnormal DNA methylation occurs in the brain within a
few weeks after birth when infant mice are not well cared
for by the mother, leading to abnormal behaviors in infancy
]. This suggests that human pervasive developmental
disorders can be caused by an epigenetic failure due to an
environmental factor. Although numerous genetic studies
in pervasive developmental disorders have been performed,
to date few genes have been identified. Taken together,
pervasive developmental disorders may not be caused
simply by alterations in DNA sequence (i.e., mutation), but
also by alterations in epigenetic regulation. This hypothesis
is supported by evidence that a repair system has only been
identified to date for DNA sequence – but not for
epigenetic information [
Nutritional factors can also alter epigenetic systems.
Folic acid is an essential substitute for DNA methylation,
and the excess administration of folic acid to pregnant mice
causes abnormal DNA methylation of a gene for
pigmentation in the fetuses [
]. Nutrition lacking folic acid also
alters the expression of imprinting genes in mice [
DNA methylation substitutes (folic acid, Vitamin B6,
Vitamin B12, S-adenosyl methionine) are effective
empirically in the treatment of autistic disorders and
]. Moretti et al.  recently identified
low levels of folic acid in the cerebral fluid samples of
Rett-like patients but without MECP2 mutations and found
that the administration of folic acid was an effective
Fig. 2 Effect of epigenetic changes during fetal development. It has
recently been hypothesized that poor nutrition in the uterus of a
pregnant woman turns off the economy genes via the epigenetic
mechanism, resulting in metabolic syndrome in adulthood due to
obesity caused by the energy storage condition under abundant
nutrition in societies of advanced nations [
treatment for these patients. Low levels of folic acid do not
necessarily indicate hypomethylation of DNA, but if it is
the case, the gene that shows hypomethylation will
be useful as a genetic indicator of folic acid treatment.
In a similar context, folic acid was administered for a
neuromuscular disease, facioscapulohumeral muscular
dystrophy, in which hypomethylation was found in its
causative gene region [
]; however, these researchers
were unable to demonstrate that folic acid treatment had a
significant effect. In the future, we may have to establish a
methylation therapeutic method specific for certain genes
related to a specific epigenetic disease. One such candidate
molecule will be double-strand small RNAs designed in the
promoter regions of causative genes [
The presence of environmental stress during the fetal
period has been suggested as a mechanism that may alter
gene expression patterns epigenetically, with these altered
infants developing metabolic syndrome in adulthood [
(Fig. 2). Figure 3 summarizes current understanding
and hypotheses of the linkage between various epigenetic
diseases and the possibly associated environmental
DNA methylation is dramatically changed at the cell
differentiation step during early development. At this step, the
pluripotency-associated genes are epigenetically
inactivated, and the permanent type of epigenetic silencing
safeguards against the accidental expression of these genes
in differentiated cells because that might lead to
dedifferentiation and to a predisposition to cancer [
]. Thus, it has
a long held belief that the properly determined epigenetic
pattern is maintained in each cell type for the life-time of
However, as discussed above, the epigenetic control
may change at different stages during a life-time due to an
environmental factor. An environmental stress (i.e., mental
stress) alters DNA methylation in brain cells after birth in
], suggesting that a similar phenomenon may occur
in humans. If so, such an epigenetic event induced by an
environmental factor in infancy may contribute to the
occurrence of pervasive developmental disorders. Hyman
et al. [
] and Baird et al. [
] have reported that the rates
of pervasive developmental disorders and those of autism
have recently increased. There is also increasing evidence
that behavioral and educational interventions with young
patients may improve developmental and behavioral
outcomes and that basic deficits in play and communication
may be therapeutically modified [
]. Therefore, when we
fully understand the role of the epigenetic mechanism in
pervasive developmental disorders, we will be able to
identify associated environmental factors and establish an
epigenetics-oriented new therapy.
Acknowledgements The author expresses his gratitude to Prof.
Kanehisa Morimoto for planning the symposium of epigenetic
medicine at the 77th Annual Meeting of the Japanese Society for Hygiene
(Osaka) and his thanks to Prof. Yasuhito Yuasa for the opportunity to
write this review.
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