Download Genomic imprinting and human disease

© The Authors Journal compilation © 2010 Biochemical Society
Essays Biochem. (2010) 48, 187–200; doi:10.1042/BSE0480187
12
Genomic imprinting and
human disease
Ryutaro Hirasawa and Robert Feil1
Institute of Molecular Genetics, CNRS UMR-5535 and the University
of Montpellier, 1919, route de Mende, 34293 Montpellier, France
Abstract
In many epigenetic phenomena, covalent modifications on DNA and
chromatin mediate somatically heritable patterns of gene expression. Genomic
imprinting is a classical example of epigenetic regulation in mammals.
To date, more than 100 imprinted genes have been identified in humans
and mice. Many of these are involved in foetal growth and development,
others control behaviour. Mono-allelic expression of imprinted genes
depends on whether the gene is inherited from the mother or the father.
This remarkable pattern of expression is controlled by specialized sequence
elements called ICRs (imprinting control regions). ICRs are marked by
DNA methylation on one of the two parental alleles. These allelic marks
originate from either the maternal or the paternal germ line. Perturbation of
the allelic DNA methylation at ICRs is causally involved in several human
diseases, including the Beckwith–Wiedemann and Silver–Russell syndromes,
associated with aberrant foetal growth. Perturbed imprinted gene expression
is also implicated in the neuro-developmental disorders Prader–Willi
syndrome and Angelman syndrome. Embryo culture and human-assisted
reproduction procedures can increase the occurrence of imprinting-related
disorders. Recent research shows that, besides DNA methylation, covalent
histone modifications and non-histone proteins also contribute to imprinting
regulation. The involvement of imprinting in specific human pathologies
1To
whom correspondence should be addressed (email [email protected]).
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(and in cancer) emphasizes the need to further explore the underlying
molecular mechanisms.
Introduction
Mammalian genomic imprinting is an epigenetic marking phenomenon leading
to mono-allelic expression of a subset of genes [1]. Mono-allelic expression
depends entirely on the parental origin of the gene. Thus some imprinted genes
are expressed only from the maternally inherited allele, whereas others are
expressed exclusively from the paternal allele. Approximately 130 autosomal
imprinted genes have been identified in the mouse so far (see http://www.
mousebook.org/catalogue.php?catalog=imprinting). Many of these are imprinted
in humans as well (http://igc.otago.ac.nz/home.html). The majority of the
known imprinted genes are arranged in clusters of several tens up to thousands
of kilobases (kb) in size. Imprinted gene expression across these evolutionarily
conserved clusters is regulated by ICRs (imprinting control regions), essential
DNA sequence elements that are up to several kilobases in size. ICRs are
CpG-rich regions that are methylated only on one of the two parental alleles.
Therefore they are also referred to as DMRs (differentially methylated regions).
Imprinted genes are involved in various biological processes. Not surprisingly, therefore, perturbation of their expression can cause embryonic or
postnatal lethality, aberrant growth and, in some cases, abnormal behaviour. In
humans, genetic alterations at imprinted domains include UPDs (uniparental
disomies), in which one pair of chromosomes is inherited from one of the parents only. This alters the levels of expression of the imprinted genes concerned,
causing various complex diseases. UPDs affecting entire chromosomes, or
portions of chromosomes, are causally involved in the neuro-behavioural disorder PWS (Prader–Willi syndrome) and in the BWS (Beckwith–Wiedemann
syndrome), associated with aberrant foetal growth (see below).
In genomic imprinting, covalent modifications are put on to specific loci
during male or female gametogenesis. These epigenetic marks, which confer
a ‘memory’ of the parental origin to these loci, are called ‘imprints’. Detailed
molecular and genetic studies have determined that imprinting is controlled by cytosine methylation at ICRs. After fertilization, DNA methylation
imprints at ICRs are maintained throughout embryonic development and
postnatal life [1]. In the developing embryo, these marks confer parental-allele-specific expression to close-by genes. In the primordial germ cells of the
developing embryo, however, all pre-existing methylation at ICRs is erased,
and new imprints are re-established at later stages, thus completing the
imprinting cycle [1] (Figure 1).
DNA methylation in mammals is regulated by members of the DNMT
(DNA methyltransferase) family [1]. Several laboratories discovered that
DNMTs play essential roles in the establishment and maintenance of methylation imprints. Factors that interact with DNMTs, or are associated with DNA
methylation, are important for the imprinting process as well. In the first part
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Figure 1. Establishment, maintenance and erasure of parental imprints
DNA methylation imprints are established at ICRs during oogenesis (maternal imprints) or
spermatogenesis (paternal imprints). After fertilization, parental imprints are maintained in all
somatic cells and tissues throughout development. Conversely, in the newly forming germ cells
of the embryo, they are erased and methylation imprints will become established later during
gametogenesis, according to the sex of the embryo.
of this chapter, we summarize the different factors known to be involved in
the acquisition and maintenance of DNA methylation imprints. In the second
part, we provide examples of human diseases that are caused by genetic or epigenetic perturbation of imprinted genes (summarized in Table 1).
Factors involved in the acquisition and
maintenance of imprints
In the mouse, establishment of DNA methylation imprints in the developing
male germ cells initiates at E (embryonic day) 14.5–15.5. Paternal ICRs
become fully methylated several days later (at E17.5–18.5) when final sperm
cell differentiation ensues. Establishment of methylation imprints in the female
germ cells takes place in adult life only, during the final stages of oogenesis.
The de novo DNMT Dnmt3a and a related co-factor called Dnmt3L are
required for imprint establishment in both of the germ lines [2,3]. Although
Dnmt3L does not have methyltransferase activity, it brings about the catalytic
action of Dnmt3a, most likely by recruiting Dnmt3a to the chromatin [4].
Another de novo methyltransferase, Dnmt3b, is also required for embryonic
development, but it is not essential for imprint establishment.
Previous work suggests that histone modifications also influence imprint
establishment in germ cells. Dnmt3L selectively binds to histone H3 in vitro,
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Characteristics
Neurological disorder
Neuro-developmental disorder
Growth disorder
Growth retardation
Hormonal and metabolic disorder
Developmental disorders
Developmental disorders
Hormonal and metabolic disorder
Disease
AS
PWS
BWS
SRS
TNDM
Maternal UPD14 syndrome
Paternal UPD14 syndrome
AHO, PHP
20q13
14q32
14q32
GNAS
RTL1
RTL1, DLK1
PLAGL1, ZFP57
GRB10?
7p12
6q24 6p22
IGF2,
IGF2, CDKN1C
SNRPN, NDN
UBE3A
Genes involved
11p15
11p15
15q11-13
15q11-13
Chromosomal region
Table 1. Genetic and epigenetic alterations in imprinting-related pathologies
GNAS locus
UPD14
Imprinting errors and mutations at the
UPD14
Imprinting errors at 14q32 paternal
6q24 region, mutations in the ZFP57 gene
Imprinting errors at 14q32 maternal
UPD7, 7p duplications
Paternal UPD6, paternal duplication of
methylation at the IGF2-H19 ICR maternal
translocations affecting 11p15
Maternal duplication of 11p15, loss of
gain of methylation at the H19-IGF2 ICR,
KvDMR1 ICR, mutations in CDKN1C gene,
ICR
Paternal UPD11, loss of methylation at
UPD15, imprint alterations at the SNRPN
imprinting defects at the SNRPN ICR
Paternal 15q11-13 deletion, maternal
UPD15, mutations at the UEB3A gene,
Maternal 15q11-13 deletion, paternal
Major causes
R. Hirasawa and R. Feil
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but only when H3 Lys4 (H3K4) is not methylated [5]. Therefore H3K4 methylation could prevent acquisition of de novo DNA methylation. In agreement
with this hypothesis, several maternal ICRs are enriched in H3K4 dimethylation (H3K4me2) in male germ cells (where they do not become methylated)
[6]. More recently, it was reported that H3K4 demethylation by KDM1B, a
lysine demethylase, is an essential first step in the acquisition of DNA methylation imprints at some ICRs in oocytes [7] (Figure 2). Besides the absence
of H3K4 methylation, the presence of other specific histone modifications
could facilitate Dnmt3a recruitment to its target loci. Symmetrical dimethylation of histone H4 Arg3 (H4R3me2s) is one possible candidate. Using the
β-Globin locus as a model, it was recently shown that Dnmt3a recognizes
Prmt5-mediated H4R3me2s through its PHD (plant homeodomain) motif.
This recognition triggers acquisition of new DNA methylation at this locus in
developing blood cells [8].
Features of the DNA sequences of ICRs might contribute to the acquisition of DNA methylation as well. Structural studies on the Dnmt3a–Dnmt3L
complex provided insights into how these proteins might recognize and
methylate DNA [4]. Specifically, the characteristics of the tetrameric protein
structure formed of two Dnmt3a and two Dnmt3L proteins suggest that DNA
sequences with a series of CpG dinucleotides at 8–10 bp intervals could be the
preferred substrate. Interestingly, such a regular spacing between CpGs has
been detected at many ICRs [4].
Figure 2. Histone methylation guides the acquisition of DNA methylation imprints
In the nucleus, genomic DNA (black) is wrapped around the histone proteins (brown) that constitute the nucleosomes. Imprint acquisition is mediated by DNMT3A which is targeted to ICRs
by its partner protein DNMT3L. H4K4 methylation prevents binding of DNMT3A–DNMT3L
complexes to chromatin, and can thus prevent acquisition of methylation imprints in germ cells.
Concordantly, KDM1B, an enzyme that removes methylation from H3K4, is required for imprint
establishment at several ICRs.
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Non-histone proteins also contribute to the specificity of imprint establishment. A recent mouse targeting study showed that Zfp57, a zinc-finger
domain protein, is involved in oocyte-specific imprint establishment at the
Snrpn ICR [9]. Furthermore, a screen for genetic mutations in familial cases of
BWS led to the identification of NLRP2 (NALP2), another protein that contributes to the establishment of maternal imprints [10]. The molecular function
of NLRP2 is not clear. Genetic mutations in a related gene, NLRP7 (NALP7),
had been associated before with familial cases of complete hydatidiform mole,
a severe developmental condition in which epigenetic abnormalities are apparent at all of the maternal ICRs [11].
Somatic maintenance of parental imprints through
development
Faithful maintenance of imprints is essential for normal development. Its
perturbation is causally involved in different human pathologies and is
thought to be an early contributing factor in cancer. This raises the question
of how ICRs maintain their allelic DNA methylation in somatic cells and
tissues. Continuous expression of Dnmt1 is clearly essential, as well as
its level of expression. Conditional targeting of Dnmt1 has shown that,
during the critical pre-implantation period, maternal and zygotic Dnmt1
are sufficient to maintain methylation imprints [12]. Np95 (also known
as Uhrf1) binds to methylated DNA through its SRA (SET and RING
finger-associated) domain and forms complexes with Dnmt1 to mediate
Dnmt1 loading to replicating heterochromatic regions. Consequently, Np95
maintains global and local DNA methylation and thereby represses imprinted
genes [13].
There is growing evidence for involvement of other proteins, which are
not part of the DNA methylation machinery. Zfp57, for instance, contributes to embryonic maintenance of maternal imprints. In embryos lacking
Zfp57, methylation is largely lost from the Snrpn ICR and partial losses of
methylation occur at other ICRs as well [9]. Support for ZFP57 involvement
in human disease has come from studies on patients with TNDM (transient
neonatal diabetes mellitus) [14]. In approximately one-fifth of cases, TNDM
is caused by loss of DNA methylation at the ICR of the imprinted PLAGL1
gene (also called ZAC1) on chromosome 6q24. This subgroup of TNDM
patients shows concomitant methylation losses at other ICRs, suggesting that
ZFP57 interacts with multiple ICRs, probably through recruitment of repressive protein complexes. In one genetic study, the ZFP57 locus was found to
be genetically homozygous in patients, but not in unaffected family members.
Subsequent identification of deleterious genetic mutations in the gene confirmed its causal involvement in TNDM. Another key protein involved in
imprint maintenance is PGC7/Stella, a maternal factor which is essential for
early development and protects against loss of DNA methylation at several
imprinted loci [15].
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Genomic imprinting, assisted reproduction and
human disease
Several developmental and growth disorders in humans are caused by
epigenetic perturbations of imprints that probably arise during the early stages
of development. Although the underlying mechanisms are unknown, the
occurrence of these ‘epimutations’ could be linked to the parental genomes’
global reprogramming in the zygote at pre-implantation. Perhaps DNA
methylation patterns are not yet firmly fixed in the non-committed cells of
early embryos unlike differentiated cells at later developmental stages. Indeed,
manipulation and culture of pre-implantation embryos and embryonic
stem cells can readily perturb imprints, affecting imprinted expression
and phenotype later in development [16,17]. Concordantly, the incidence
of certain imprinting diseases appears to be increased following assisted
reproduction. Different ARTs (assisted reproduction technologies) can affect
the epigenetic regulation of imprinted genes in the babies born [18]. ART
had been long suspected to increase the occurrence of classical imprinting
syndromes and recent studies have indeed reported their increase, particularly
of the BWS and AS (Angelman syndrome), in babies born following ARTs
[17–19]. The underlying causal mechanisms remain unknown. However,
since methylation defects can occur concomitantly at several imprinted loci in
individual patients, there could be involvement of factors regulating multiple
ICRs.
Prader–Willi syndrome and Angelman syndrome
PWS and AS were the first reported imprinting disorders in humans.
Genetically, they map to human chromosome 15q11-q13, to the so-called
PWS/AS chromosomal region (Figure 3A). This region comprises a large
cluster of imprinted genes which are causally involved in these syndromes.
All imprinted genes in this cluster are expressed highly in the brain, from the
paternally inherited chromosome, except one, UBE3A, which is expressed
from the maternal allele. PWS affects one in 10000 children and is characterized
by neonatal muscular hypotonia, hyperphagia and early childhood obesity,
hypogonadism, short stature, small hands and feet, and mild mental retardation
[19]. Often this pathology is caused by paternal deletion or maternal UPD
of the PWS/AS region, leading to loss of expression of all of the paternally
expressed genes in the cluster.
AS has rather opposite clinical features and is characterized by developmental delay, ataxia, absence of speech, severe mental retardation, jerky arm movements and inappropriate laughter [19]. In contrast with PWS, AS is often caused
by maternal deletion of 15q11-q13. Whereas PWS is thought to be a contiguous
gene syndrome with several imprinted (paternally expressed) genes causing the
disorder, AS is caused by loss-of-expression of a single imprinted gene, UBE3A,
which encodes an ubiquitin ligase involved in brain development.
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Figure 3. (Continued on next page)
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The promoter and first exon of the SNRPN gene constitute the ICR of
the PWS/AS domain. This ICR has a maternally derived DNA methylation
imprint. Human studies indicate that this imprint becomes established after
fertilization only. Thus the de novo DNA methylation machinery somehow
recognizes the right parental allele in the zygote. Based on transgenic mouse
models, it was proposed that this recognition involves a maternally derived
chromatin signature [20]. In the mouse, the Snrpn ICR acquires its methylation imprint at an earlier stage, during the maturation of the oocyte, and this
involves both Dnmt3a and Dnmt3L. If Dnmt3L is absent during oogenesis
(in Dnmt3L-/- females), the imprint is not established. However, ICR methylation is later detected in some of the offspring of Dnmt3L-deficient females.
This intriguing observation supports the idea that, also in the mouse, there
could be a chromatin signature which is inherited from the oocyte and mediates imprint acquisition at the Snrpn ICR during early development [21].
Silver–Russell and Beckwith–Wiedemann syndromes
The foetal growth disorders SRS (Silver–Russell syndrome) and BWS
map to chromosome 11p15 and have opposite phenotypes. Whereas SRS
is characterized by intra-uterine growth restriction, BWS shows foetal
overgrowth [19]. Chromosome 11p15 comprises two neighbouring imprinting
clusters that are crucial for the control of foetal growth. The most proximal one
is the large KCNQ1 cluster that comprises CDKN1C, a negative regulator of
cellular proliferation. The other cluster is small and comprises IGF2 (insulinlike growth factor 2), a major regulator of foetal growth in mammals. SRS and
BWS are most frequently caused by epimutations at the ICRs that control the
KCNQ1 and IGF2 domains (Figure 3B), whereas 11p15 duplications and other
genetic changes are infrequent [19,22,23,24].
Figure 3. Pathogenic mechanisms in imprinting-related human disorders
(A) PWS and AS map to chromosome 15q11-q13. This region comprises a large imprinted
domain controlled by the SNRPN ICR, deletion of which leads to PWS. A region at 30 kb
upstream of the ICR is essential for the acquisition of its maternal DNA methylation. Deletion
of this region gives rise to AS. Most of the genes in the domain are activated by the ICR on the
paternal chromosome, including paternally expressed SnoRNAs (small nucleolar RNAs) and
microRNAs that are generated from a transcript that originates at the SNRPN gene. A paternally
expressed antisense RNA, UBE3Aas, is part of this long transcription unit as well. This antisense
RNA is thought to repress UBE3A, leading to its maternal allele-specific expression. PWS and
AS can be caused by different types of genetic and epigenetic mutations. The approximate frequencies of the known causal alterations are indicated in the lower part of the Figure. Note that
in AS, approximately 20% of cases are caused by as yet unknown mechanism(s). (B) Epigenetic
alterations at chromosome 11p15 involved in BWS and SRS. The IGF2-H19 domain has a paternally methylated ICR. Early embryonic gain of methylation at this ICR gives rise to (bi-allelic IGF2
expression and) the BWS overgrowth syndrome. Embryonic loss of DNA methylation, in contrast, leads to (loss of IGF2 expression and) the intra-uterine growth restriction syndrome SRS.
The neighbouring KCNQ1 domain comprises the maternally expressed gene CDKN1C, a negative
regulator of growth. Loss of methylation at the intragenic ICR of this domain induces repression
on both the parental chromosomes [through the ncRNA (non-coding RNA) KCNQ1OT1]. This
leads to loss of CDKN1C expression, the most common cause of BWS.
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SRS is a sporadic disorder with intra-uterine and postnatal growth retardation, facial dysmorphism, fifth finger clinodactily, feeding difficulties and,
often, body asymmetry. Its incidence is 1 in 50000 births [21]. Recent studies
show that in approximately half of the patients, DNA methylation is lost at
the ICR controlling the IGF2 imprinted domain. This leads to loss of IGF2
expression, explaining the severe growth retardation. Approximately 10%
of SRS patients have maternal UPD of chromosome 7. It is unclear which
imprinted gene(s) could be causally involved in these patients, but GRB10
(growth-factor-receptor-binding protein 10) is one of the candidates [19].
Conversely, BWS is characterized by overgrowth and increased risk of
childhood cancers including Wilms’ tumour of the kidney. Its diagnostic features are high birth weight and length, macroglossia, midline abdominal wall
defects, ear creases or ear pits, and neonatal hypoglycaemia after birth [19].
It is mostly a sporadic disease and approximately 10% of BWS have the exact
opposite epigenetic alteration at the ICR of the IGF2 locus than the one
observed in SRS. These patients show gain of methylation at this ICR, on the
parental allele which is normally unmethylated. This induces bi-allelic expression (and increased protein levels) of IGF2 [22]. BWS arises not only from epigenetic alterations at the ICR of the IGF2 locus, but also through altered DNA
methylation at the ICR which controls the neighbouring KCNQ1 domain. In
approximately half of the patients, methylation is lost at this intronic ICR,
which leads to bi-allelic silencing of CDKN1C, causing the observed overgrowth in this class of patients.
Transient neonatal diabetes mellitus
TNDM occurs in growth-retarded neonates who show persistent hyperglycaemia
within the first 6 weeks of life. It has an incidence of ~1 in 400000 births.
Affected babies require exogenous insulin therapy for a mean duration of 3
months while endogenous insulin levels are either extremely low or undetectable.
Recovery is usually complete by 18 months of age, although some patients
relapse and develop diabetes later in life. Paternal UPD of chromosome 6 and
large paternal duplications of 6q24 have been linked to TNDM. This led to the
hypothesis that TNDM is caused by overexpression of an imprinted gene located
in a ~5.4 Mb region on chromosome 6q24. The disease was found subsequently to
involve an imprinted locus that comprises the paternally expressed transcription
factor gene PLAGL1. This locus has a putative ICR with a maternal DNA
methylation imprint. In the majority of patients with TNDM, there is pronounced
loss of methylation at this ICR, leading to bi-allelic PLAGL1 expression [22].
Interestingly, PLAGL1 regulates the expression of other imprinted genes,
including IGF2 and CDKN1C, and influences the transcriptional activity of
KvDMR1, the ICR that controls the KCNQ1 domain [25]. It is unknown which
factors induce loss of DNA methylation at the PLAGL1 ICR, which may occur
in BWS as well [24]. However, a recent study shows that the zinc finger protein
ZFP57 contributes to the maintenance of methylation at this (and other) ICRs [9].
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Pseudohypoparathyroidism and Albright’s
hereditary osteodystrophy
The GNAS locus on chromosome 20q13.2-13.3 is a complex locus that
produces multiple transcripts through the use of alternative promoters and
splicing. Genetic and epigenetic mutations at the GNAS locus are involved in
different forms of PHP (pseudohypoparathyroidism), a disorder characterized
by lack of responsiveness to PTH (parathyroid hormone) and additional
hormones. Patients have short stature, rounded faces and, often, mild mental
retardation. There are two main subtypes of PHP. PHP-type 1a patients show
resistance to PTH and display a combination of physical features called AHO
(Albright’s hereditary osteodystrophy). In these patients, the disease is mostly
caused by heterozygous inactivating mutations in the GNAS gene. The parental
origin of the mutations determines the severity of the hormone resistance. PHP
type-2 patients do not have AHO, and the great majority of cases are caused
by loss of DNA methylation at one of the ICRs of the GNAS locus.
Uniparental disomy 14
Maternal UPD of chromosome 14 (UPD14mat) causes pre- and post-natal
growth retardation, congenital hypotonia, joint laxity, motor delay and
mild mental retardation. Paternal UPD14 (UPD14pat) has a more severe
phenotype, including polyhydramnios, thoracic and abdominal wall defects,
growth retardation and severe developmental delay. Cases of segmental
UPD14 indicate that the distal portion of chromosome 14q is the critical
region. The 14q32.2 region comprises an imprinting cluster that includes the
paternally expressed DLK1 and RTL1 and the maternally expressed GTL2
and RTL1as (RTL1 antisense) genes, all under the control of a single ICR.
The clinical phenotypes linked to maternal and paternal UPD14 appear to be
caused by deregulation of these imprinted genes through several mechanisms.
Gene targeting studies in mice suggest that the ICR has an important cis-acting
regulatory function on the maternally inherited chromosome, and that
excessive RTL1 and decreased DLK1 and RTL1 expression are relevant to
UPD14pat and UPD14mat phenotypes respectively [26]. The imprinted
14q32.2 region is also associated with increased risk of Type 1 diabetes [27].
Future directions
In this overview on imprinting and its deregulation in disease we focused on
ICRs, the key regulatory elements involved. Epigenetic imprints at ICRs are
established in one of the two germ lines and, after fertilization, are maintained
throughout development. In the newly formed germ cells of the developing
embryo, however, epigenetic imprints are removed to allow subsequent
establishment of new imprints for the next generation. These sequential
events – establishment, maintenance and erasure – constitute the developmental
cycle of imprinting (Figure 1). Importantly, imprinting-related pathologies are
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often associated with epigenetic changes (Table 1). The discussed examples
of such epimutations all concern the maintenance of imprints in the early
embryo. Although maintenance mechanisms remain poorly understood,
recent data indicate that this process also involves non-histone proteins and is
linked to specific patterns of histone methylation. Future research will identify
the specific histone methyltransferases (and demethylases) involved. Their
functional importance in the regulation of imprints needs then to be explored
in cells and animals, in a similar manner as has been done for DNMTs.
There is a growing interest in whether assisted reproduction could affect
imprinted gene loci and thereby the development and health of the babies
born. This important question emerged after it was demonstrated in mice and
in ruminant species, that embryo culture can heritably affect imprinted gene
expression. Various studies link assisted reproduction to increased frequencies of imprinting syndromes. These disorders occur at low frequencies in
the general population and are still very rare following assisted reproduction.
Other risks, including low birth weight and poor postnatal development, are
significantly higher. In the coming years it would be relevant to explore at
the genome-wide level to what extent DNA methylation and other epigenetic
modifications are altered by assisted reproduction.
During the coming decade, genetic studies in humans and targeting
experiments in mice will undoubtedly provide new important insights into
the sequence elements and the protein factors that control imprinted genes.
Detailed biochemical studies on the protein complexes involved and on how
they modify chromatin and DNA will be required to better understand why
epigenetic mutations arise in cultured cells and embryos, and sometimes during
early development, leading to diverse pathologies.
Summary
•
•
•
•
•
•
•
Genomic imprinting is an epigenetic mechanism leading to monoallelic expression of certain genes depending on the parental origin of
the allele.
Imprinted genes are organized in conserved clusters. Their allelic
expression is controlled by ICRs.
ICRs are marked by parental allele-specific DNA methylation that is
established during either oogenesis or spermatogenesis.
In somatic cells, ICRs also show allele-specific histone methylation.
After fertilization, the allelic chromatin imprints at ICR are maintained throughout development, in all the cell lineages.
Perturbation of the epigenetic imprints at ICRs leads to perturbed gene
expression and is causally involved in several human diseases.
Environmental stresses, such as embryo and cell culture, or assisted
reproduction technologies, can also readily perturb imprints, with
long-term consequences for gene expression and phenotype.
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