Human Molecular Genetics, 2003, Vol. 12, Review Issue 1 R61-R68
DOI: 10.1093/hmg/ddg067
© 2003 Oxford University Press
Beckwith–Wiedemann syndrome demonstrates a role for epigenetic control of normal development
Rosanna Weksberg1,3,4,5,6,*,
Adam C. Smith1,6,
Jeremy Squire2,7 and
Paul Sadowski3
1Institute of Medical Sciences,
2Department of Laboratory Medicine and Pathobiology,
3Department of Medical Genetics and Microbiology and
4Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada,
5Division of Clinical and Metabolic Genetics and
6The Research Institute Programme in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada and
7Ontario Cancer Institute, Toronto, Ontario, Canada
Received January 3, 2003; Revised January 10, 2003; Accepted January 15, 2003
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ABSTRACT
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The Beckwith–Wiedemann syndrome (BWS) is characterized
by somatic overgrowth and a predisposition to pediatric embryonal
tumors. It is associated with genetic or epigenetic abnormalities
in a cluster of imprinted genes found within a genomic region
of approximately one megabase on human chromosome 11p15. Imprinted
genes are expressed preferentially or exclusively from either
the paternal or maternal allele. The 11p15 region is organized
into two imprinted domains in which genomic imprinting is controlled
by separate ‘imprinting control regions’. Twenty-five
to 50% of BWS patients have biallelic rather than monoallelic
expression of the insulin-like growth factor 2 (
IGF2) gene.
Another 50% of patients have an epigenetic mutation resulting
in loss of imprinting of a transcript called
KCNQ1OT1. Each
of these genes resides in one of the two imprinted domains that
appear to be subject to developmental dysregulation in BWS.
In this review, we discuss the insights that the study of BWS
have contributed to our understanding of the mechanisms of growth
control, oncogenesis and genomic imprinting. Specifically, methylation
and chromatin modification may coordinate the expression of
closely linked imprinted genes. Finally, we discuss how knowledge
of epigenetic mechanisms associated with the early stages of
embryogenesis suggest caution in the current debate surrounding
assisted reproductive and cloning technologies.
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INTRODUCTION
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Beckwith–Wiedemann syndrome (BWS) was first described
four decades ago as a disorder of growth regulation manifesting
as somatic overgrowth, congenital malformations and tumor predisposition.
Although the majority of cases are sporadic, a small number
of pedigrees with autosomal dominant inheritance demonstrated
linkage to 11p15 (
1,
2). The involvement of genomic imprinting
in the phenotype was suggested by the preferential loss of maternal
alleles in BWS-related tumors (
3) and the maternal inheritance
of the autosomal dominant forms of the condition (
4). In fact,
BWS and its related tumors provide a unique opportunity to investigate
the role of genomic imprinting in normal growth and development.
BWS is a clinically heterogeneous disorder. The presenting findings may include macrosomia (prenatal and/or postnatal gigantism), hemihyperplasia, macroglossia, abdominal wall defects, embryonal tumors, ear anomalies, visceromegaly, renal abnormalities and neonatal hypoglycemia. Additional supportive findings may include polyhydramnios and prematurity, enlarged placenta, cardiomegaly, hemangiomata, cleft palate, advanced bone age and characteristic facies with midfacial hypoplasia and infraorbital creases. The characteristic facial appearance tends to regress over time (5).
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WHAT IS GENOMIC IMPRINTING?
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While most autosomal genes are expressed from both alleles,
there is a subset of genes that are imprinted, i.e. they are
expressed from only one allele (the paternal or maternal copy)
(for recent reviews see
6–
10). The molecular basis of
imprinting is said to be ‘epigenetic’: two alleles
that are identical in nucleotide sequence but of opposite parental
origin are regulated differently in the same nucleus. This process
is reversible. The silent, imprinted allele can be reactivated
when passed through the germ line of the opposite parental sex
and the active allele is silenced. Imprinted genes tend to occur
in large clusters of greater than 1 Mb in length. One such
cluster is located on 11p15 where dysregulation of imprinted
genes is causally related to BWS.
Imprinting of the genes within these domains is regulated in cis by one or more imprinting center(s). Imprinting centers are thought to generate parent-of-origin-specific chromatin states that are propagated bidirectionally over several hundred kilobases of DNA to regulate the resetting of the imprint in the germline (11). The imprinting centers are likely also involved in maintaining imprints in somatic cells. Imprinting center mutations, therefore, should result in the failure to reset imprints, leading to inheritance of an inappropriate ‘epigenotype’ across an interval of up to one megabase (12).
Imprinted regions have been found to show a number of common characteristic features. These include differential DNA methylation, allele-specific RNA transcription, antisense transcripts, histone modifications, as well as differences in replication timing. Recent work has focused on the regulatory role of the parent of origin-specific differentially methylated regions (DMRs). A differentially methylated region is a DNA sequence that bears a CpG methylation mark that is specific to the chromosomal parent-of-origin. Such DMRs may be maternally or paternally methylated. Usually, although not always, the methylated allele is the silenced (imprinted) allele. Changes in the parent-of-origin-specific methylation of the DMR constitute an epigenetic lesion since they do not involve a change in the nucleotide sequence.
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IMPRINTED GENES ON 11p15
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The imprinted cluster of genes on 11p15 contains at least 12
imprinted genes (
13–
18). The 11p15 region has been divided
into two distinct domains that are thought to be regulated by
two imprinting centers separated by a non-imprinted region (Fig.
1).
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Figure 1. Map of the 11p15 imprinted region. Maternally expressed genes are shown in red and paternally expressed genes are shown in blue. Genes shown in gray are not imprinted. The direction of transcription is indicated by the square arrows. Hatch marks indicate regions of 11p15 not shown. Model of imprint regulation for domains 1 and 2 on 11p15. Known regulatory mechanisms shown by arced arrows and dashed arrows indicate proposed regulatory pathways. DMR1 and DMR2 locations are indicated by blue and red colored boxes, respectively. Methylation is indicated by a circle containing a methyl-group (CH3).
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Domain 1
Domain 1 contains the imprinted genes insulin-like growth factor
2 (
IGF2) and
H19, and a differentially methylated region, ‘DMR1’
postulated to be an imprinting center. The maternally expressed
H19 gene encodes an apparently untranslated polII transcript,
and the
IGF2 gene encodes a paternally expressed fetal growth
factor. Up-regulation of
IGF2 is thought to be important in
the pathogenesis of BWS (
19–
27) and a variety of tumors
(
28,
29). The expression profile of
IGF2 in normal development
parallels the spectrum of organs/systems affected in patients
with BWS (
30). Increased expression of
IGF2 may be caused by
paternal chromosome duplications of chromosome 11p15, paternal
uniparental disomy (two copies of the paternal chromosome region),
or alterations to differential methylation (
3,
31–
33).
Significantly, transgenic mice that overexpress
IGF2 exhibit
some but not all of the features of BWS (overgrowth, macroglossia)
(
20).
The H19 and IGF2 genes compete for a common set of downstream enhancers located 3' of the H19 gene (34–36). DMR1 is located 2 kb upstream of the mouse H19 gene and regulates the reciprocal imprinted expression of H19 and IGF2 gene in domain 1 by functioning as a chromatin boundary element or insulator (36–43) (Fig. 1). On the maternal chromosome, DMR1 is unmethylated, permitting the binding of a zinc finger protein called CTCF. Binding of CTCF blocks access of the IGF2 promoter to the downstream enhancers. Thus, the maternal copy of H19 is activated by these enhancers and is transcribed. Methylation of the paternal copy of DMR1 and the H19 promoter are thought not only to silence the H19 promoter but also to prevent binding of the CTCF protein to DMR1. As a result, the IGF2 promoter can access the downstream enhancers and H19 is silenced (42). Rarely, cases of BWS have hypermethylation of the paternal H19 promoter that causes biallelic IGF2 expression (44).
Domain 2
In Domain 2, there are six known imprinted genes including CDKN1C (p57KIP2), a maternally expressed gene that encodes a cyclin-dependent kinase inhibitor and negatively regulates cell proliferation (45). In tumors, CDKN1C shows aberrant methylation associated with cell cycle dysregulation (46–48); however, this gene is rarely mutated in tumors (49,50). Interestingly, mutations in CDKN1C do cause BWS (51–53) and are often associated with autosomal dominant inheritance of the syndrome. TSSC3 (IPL) (54) is a maternally expressed gene that shows homology to Tdag51, a gene involved in Fas-mediated apoptosis. Mice lacking the Impt1 gene have placental overgrowth but are otherwise normal (55). SLC22A1L (IMPT1) (56,57) is a maternally expressed gene encoding a possible organic cation transporter. Mutations of this gene have been reported in breast cancer and a rhabdomyosarcoma cell line (58). The maternally expressed KCNQ1 gene product forms part of a potassium channel. Six known translocation sites spanning the length of this gene (14,59) are strongly associated with BWS. Intron 10 of the KCNQ1 gene contains another DMR called KvDMR1 or ‘DMR2’. The paternal allele is non-methylated, permitting the paternal expression of a long transcript called KCNQ1OT1, also known as LIT1 (14,60). This transcript originates near DMR2 and is transcribed in an antisense direction to the KCNQ1 gene in which it originates. Maternal methylation of DMR2 is thought to silence maternal expression of KCNQ1OT1 and to allow expression of a number of maternally expressed genes including KCNQ1 and CDKN1C (14,60). Furthermore, a targeted deletion of the paternal KCNQ1OT1 DMR2 caused diminished expression of the KCNQ1OT1 transcript and activation of expression of the KCNQ1 and CDKN1C genes (61,62). This suggests that this antisense transcript negatively regulates in cis the expression of several genes at long-range. These data suggest that the paternally-expressed KCNQ1OT1 transcript and/or DMR2 itself can function as mediators of imprinting in domain 2. Recent evidence suggests that DMR2 has insulator activity in the mouse (63) and insulator and silencer activity in the human (Du and Sadowski, in preparation).
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MOLECULAR GENETICS OF BWS
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Current data indicate that BWS is a multigenic disorder with
clear parent-of-origin effects, and that BWS and its related
tumors result from dysregulation of several closely linked genes
associated with cell cycle and growth control on chromosome
11p15. Imprinted genes implicated in the etiology of BWS map
to the 11p15 imprinted region (Fig.
1) and include the
paternally expressed genes
IGF2 and
KCNQ1OT1, and the maternally
expressed genes
H19, CDKN1C and
KCNQ1.
Table 1 shows estimated
frequencies of known genetic/epigenetic BWS subgroups. Some
affect both domains; others are limited to one domain or the
other. However, the interaction of signals between the two domains
has not yet been explored.
Genetic lesions
The majority of BWS cases occur sporadically and have no identifiable
genetic lesion; only a minority of BWS cases have a demonstrable
constitutional DNA sequence alteration. Rarely there are 11p15
chromosome abnormalities (
33) such as chromosome 11 duplications
and translocations. The majority of the identified mutations
are in the
CDKN1C gene (
51,
64,
65). Notably,
CDKN1C mutations
are found more commonly in autosomal dominant pedigrees (
51,
64,
65)
than in sporadic cases. Mice with a targeted disruption of the
CDKN1C gene (
66,
67) exhibit some abnormalities (such as omphalocele)
similar to BWS, although overgrowth is absent. Mice with a
CDKN1C mutation and increased
IGF2 expression exhibit many of the signs
of BWS (
68).
In most BWS cases, the primary molecular change is either epigenetic or unknown. The most common epigenetic alteration associated with BWS (50% of cases) is the loss of methylation at DMR2 (60) associated with loss of imprinting of KCNQ1OT1 (14,44). Paternal 11p15 uniparental disomy occurs in 10–20% of cases (3,33). Expression of the normally silent maternal allele of IGF2 occurs in 25–50% of BWS cases (69) and for most of these cases the cause, whether genetic or epigenetic, is not known. A few of them are associated with hypermethylation of the H19 promoter and loss of maternal H19 expression, which is referred to as H19-dependent loss of imprinting of IGF2. However most cases of loss of imprinting of the IGF2 gene are associated with normal monoallelic maternal expression of the H19 gene. This is referred to as H19-independent loss of imprinting of IGF2. Unlike the mouse gene, the human IGF2 gene is thought to be differentially methylated on the maternal allele. Change in the methylation status of the IGF2 gene has not been reported for BWS. Some BWS cases with loss of imprinting for DMR2/KCNQ1OT1 also show loss of imprinting of the IGF2 gene (14,59). These data support the possibility of regulatory interactions between the two imprinted domains (Fig. 1).
Recent observations suggest that regulation of imprinting at 11p15 could be even more complex than the data already presented suggests (70). Several BWS-associated translocations disrupting KCNQ1 do not affect the methylation of DMR2 or KCNQ1OT1 expression (unpublished data), but still lead to altered IGF2 imprinting (71) and replication timing (72). The translocations may have separated some genes (e.g. IGF2, H19) from their cognate enhancers or other regulatory elements and disrupt imprinting in ways that are presently poorly understood. It is noteworthy that mice carrying a targeted chromosomal translocation whose breakpoint is between the CDKN1C and KCNQ1 genes lose expression and imprinting of Cdkn1c, Tssc3 and Slc22A1L genes (73).
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IMPRINTING AND TUMORIGENESIS
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Altered genomic imprinting may also have a role in the inactivation
of tumor suppressor genes or the overexpression of oncogenes
in certain types of cancers (
28). It is well established that
mutations in tumour suppressor genes contribute to the malignant
process when both normal alleles have lost their function. Most
commonly, an initial mutation occurs in one allele; the second
event may be a chromosomal deletion or a mitotic recombination
between the chromosome carrying the mutant allele and the chromosome
carrying the normal allele. Such changes are detected in tumors
when closely linked regions of the genome undergo loss of constitutional
heterozygosity (LOH). By convention, geneticists usually refer
to such changes presenting in somatic cells as UPD, and the
equivalent genetic change in tumors is called LOH. Some types
of tumor have been shown to undergo LOH, in a parent-of-origin
specific manner, so that either a paternal or a maternal chromosomal
region is retained (
28). Such parental bias is seen when a tumor
suppressor gene maps to an imprinted chromosomal region. If
a tumor suppressor gene is imprinted, ‘one-hit’
rather than ‘two hit’ kinetics could lead to complete
gene inactivation. Conversely, it follows that mitotic recombination
affecting a chromosomal region containing one or more imprinted
oncogenes could lead to two copies of a chromosome region derived
from one parent and a net increase in expression of any growth-promoting
sequences mapping to such a disomic region. Thus, such parental
bias in tumors exhibiting LOH may help identify the genomic
locations of tumor suppressor genes or oncogenes involved in
the malignant process, and may also provide clues concerning
their imprinting status in normal cells.
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11p15 AND INCREASED TUMOR RISK
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As described above, the molecular alterations and epigenetics
of BWS and some of the embryonal tumors associated with this
syndrome, such as Wilms' tumor and rhabdomyosarcoma, have provided
useful insights concerning the role of imprinted genes in cancer.
Just as in embryonal tumors there is often preferential retention
of paternal genes from 11p15, so paternal disomy of this same
region is also seen frequently in BWS. Dysregulation of 11p15
cell cycle proteins and growth factors seem to be strongly associated
with embryonal tumorigenesis and overgrowth, and our analysis
of the molecular genetics of domains 1 and 2 in BWS and associated
tumors has focused on the negative and positive regulators of
growth
CDKN1C (
p57kip2), and
IGF2 (
44,
69). Epigenetic changes
of the control mechanisms (DMR 1 and 2) outlined above can impact
regional regulation of constitutional gene expression of such
genes, and lead to tumor predisposition. Similarly acquired
alterations to these pivotal control mechanisms in domains 1
and 2 can take place in a single somatic cell, and can lead
to sporadic tumors. We recently reported that children with
BWS who develop embryonal tumors such as rhabdomyosarcoma and
hepatoblastoma have epigenetic changes in domain 2 (
44). In
contrast, Wilms' tumor is more strongly associated with epigenetic
alterations in domain 1 (
74–
76). Taken together these
data demonstrate that in BWS cases, embryonal tumors have two
distinct 11p15 epigenetic tumorigenic pathways that may also
reflect similar tumorigenic pathways in sporadic embryonal tumors.
Thus understanding how coordinate dysregulation of imprinted
genes takes place will be important in determining the reasons
for the variable expression of tumors in BWS and in the causation
of sporadic embryonal tumors subject to 11p15 epigenetic and
molecular lesions.
Epigenetic changes have been shown to occur in many pediatric and adult cancers (77–82). The epigenetic changes such as methylation at H19 seen in patients with BWS who develop Wilms' tumor are also seen in patients who develop Wilms' tumor without BWS. This indicates that the timing of epigenetic change may determine whether one develops a syndrome like BWS or a cancer. For example such a change in an early embryo can present as BWS and cancer predisposition whereas such a change in an embryonic precursor for an organ generates predisposition to cancer in that organ. Finally, common pediatric embryonal tumor types can also be associated with BWS including rhabdomyosarcoma, adrenal cortical carcinoma, gonadoblastoma and neuroblastoma. We have recently shown that BWS cases with these tumors exhibit loss of methylation at DMR2 and not at DMR1 (44). These data indicate that there are likely to be two distinct cancer-predisposing regions on 11p15.
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IMPRINTING OF 11p15 IN EARLY DEVELOPMENT
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BWS provides a unique opportunity to study genomic imprints
in early development. It appears that the preimplantation embryo
is a critical period in development with respect to establishment
and maintenance of imprints (
83–
86). Interestingly, we
have recently shown an early developmental epigenetic error
relating twinning and BWS (
83). We studied 10 monozygotic twin
pairs who were discordant for BWS and found loss of methylation
at DMR2 (KvDMR) and biallelic expression of
KCNQ1OT1 in all
of the affected twins. The unaffected twins did not share the
loss of methylation at DMR2 nor did these twin pairs have any
other detectable genetic or epigenetic defects on 11p15. Further,
we found a significant excess of monozygotic twinning in BWS
estimated at 8% compared with the general population occurrence
of 0.3–0.4%, whereas the occurrence of dizygotic twins
in BWS did not differ significantly from the general population.
In addition there was a significant excess of females over males
in monozygotic twin pairs (16:4). Our data suggest that there
is a critical time period in preimplantation development when
disturbance of imprinting is associated with increased likelihood
of monozygotic twinning. It is thought that two-thirds of all
monozygotic twinning occurs between embryonic days 5–9.
In fact, the process of monozygotic twinning and other environmental
disturbances in the preimplantation embryo may increase the
risk for epigenetic lesions.
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ASSISTED REPRODUCTIVE TECHNOLOGIES
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The high incidence of monozygotic twinning associated with BWS
and disruption of imprinting suggests that careful monitoring
of assisted reproductive technologies is warranted. Assisted
reproductive technologies expose the preimplantation embryo
to a variety of manipulations that could affect both rates of
monozygotic twinning and maintenance of genomic imprints. Assisted
reproductive technologies include
in vitro fertilization, intra-cytoplasmic
sperm injection and ooplasm donation, all of which could disrupt
the correct maintenance of imprints. Nuclear transfer and intracytoplasmic
sperm injection have both been shown to be associated with imprinting
defects (
87–
91). Current clinical reports regarding the
safety of assisted reproductive technologies have shown increases
in monozygotic twinning (
92,
93) but De Rycke
et al. find no
significant increase in the number of children born with defects/abnormalities
(
94). However they suggest that studies to date have only monitored
patients for two years and had relatively small sample sizes.
Recently two imprinting disorders, BWS and Angelman syndrome,
have been reported in association with assisted reproductive
technologies (
89–
91). Additionally, it is possible that
the disruption of the epigenetic state of the germline may not
be immediately apparent in the offspring of the IVF pregnancy
(
94), but that problems in resetting the imprints in the germline
may occur in children in the subsequent generation (i.e. children
of parents who used assisted reproductive technology) (
94).
Careful study and follow-up of these cases is warranted considering
the body of evidence that is developing regarding the fragility
of the preimplantation embryo.
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CLONING AND IMPRINTING
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Maintenance of imprints is also an important issue in the potential
development of therapeutic strategies involving cloning. A recent
review by Sapienza (
95) and paper by Onyango
et al. (
85) investigate
the implications for using embryonic stem (ES) cells versus
embryonic germ (EG) cells in relation to the resetting of imprints
in the germline and preimplantation embryo. The variability
of methylation and expression of imprinted genes found in mouse
ES cells has raised the issue that the use of the human equivalent
of these cells for therapeutic cloning may be problematic. EG
cells originate before meiosis whereas ES cells are derived
postmeiotically. EG cells are derived from primordial germ cells
taken from the developing gonadal ridges of human fetuses, whereas
ES cells are derived from the inner cell mass of blastocyst-stage
preimplantation embryos. Although ES cells are only a few cell
divisions removed from being EG cells themselves, mouse ES cells
show great variability in their methylation (
96) and expression
of imprinted genes (
88,
97). Furthermore, it is commonly observed
that many embryos derived from ES cell are stillborn and exhibit
the ‘large offspring syndrome’ that is reminiscent
of BWS (
98). Genomic imprinting was discovered because it was
realized that the paternal and maternal contributions to the
embryo were not equal. Therefore, the utility of ES cells and
other somatically derived cell nuclei for therapeutic cloning
and nuclear transfer must be questioned until a more complete
understanding of the effects on such therapies of epigenetic
variation.
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PERSPECTIVES
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BWS provides a model system to study genomic imprinting, a process
that has a profound impact on coordinated gene expression in
development and cancer. Future profiling techniques, such as
epigenotype microarrays and genome-wide chromatin analysis will
permit a more accurate definition of the involvement of imprinted
domains in normal development. The concepts that are developed
from the study of dysregulation of imprinted domains in BWS
are likely to be generally applicable and to increase our understanding
of the role of epigenetics and chromatin structure in dysregulation
of gene expression in congenital malformations and cancer development.
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FOOTNOTES
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* To whom correspondence should be addressed at: Clinical and
Metabolic Genetics, The Hospital for Sick Children, 555 University
Avenue, Toronto, Ontario, Canada M5G 1X8. Tel: +1 4168136386;
Email:
rweksb{at}sickkids.ca 
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ABSTRACT
INTRODUCTION