Imprinting and disease

doi:10.1016/S1084-9521(02)00142-8

Seminars in Cell & Developmental Biology

Volume 14, Issue 1, February 2003, Pages 101-110

https://doi.org/10.1016/S1084-9521(02)00142-8 Get rights and content

Abstract

Deregulation of imprinted genes has been observed in a number of human diseases such as Beckwith–Wiedemann syndrome, Prader–Willi/Angelman syndromes and cancer. Imprinting diseases are characterised by complex patterns of mutations and associated phenotypes affecting pre- and postnatal growth and neurological functions. Regulation of imprinted gene expression is mediated by allele-specific epigenetic modifications of DNA and chromatin. These modifications preferentially affect central regulatory elements that control in cis over long distances allele-specific expression of several neighbouring genes. Investigations of imprinting diseases have a strong impact on biomedical research and provide interesting models for function and mechanisms of epigenetic gene control.

Introduction

Epigenetic mechanisms of gene regulation play a pivotal role in a number of human diseases including complex syndromes, multi-factorial diseases and cancer. The first complex human syndromes known to be of epigenetic origin were imprinting syndromes. The molecular studies of these syndromes significantly contributed to understanding of the molecular control of epigenetic gene regulation and their functional consequences. In this article, we will discuss examples of diseases associated with changes in imprinted gene expression and their physiological consequences. We will also discuss mechanistic and evolutionary aspects of genomic imprinting.

Genomic imprinting describes the preferential or exclusive expression of a gene from only one of the two parental alleles. The allele-specific expression of imprinted genes is based on allele-specific epigenetic modifications, so-called epigenetic marks, such as cytosine methylation and histone acetylation and methylation. In the germ cells, these marks are erased, subsequently newly established in a parent-specific manner, and maintained after fertilisation (Fig. 1).

So far, approximately 50 imprinted genes have been identified in the human and mouse genomes [1] (http://www.mgu.har.mrc.ac.uk/imprinting/imptables.html). Deregulation of imprinted genes has been observed in numerous human diseases [2]. These diseases are characterised by non-mendelian inheritance patterns that exhibit parental origin effects. The best characterised syndromes related to defects in imprinting are Beckwith–Wiedemann syndrome (BWS) on chromosome 11p and the Prader–Willi/Angelman syndromes (PWS/AS) on chromosome 15q [3], [4]. The symptoms of human imprinting diseases and observations in mouse model systems suggest that many imprinted genes play important roles in growth regulation during embryonic and postnatal development. In addition, imprinted genes also influence brain function and behaviour [4], [5]. Besides their contribution to development imprinted genes are also frequently misexpressed in cancers [2].

Section snippets

Imprinting and growth

One of the best characterised imprinting disorders affecting growth is BWS. The typical features of BWS are embryonic and placental overgrowth, macroglossia, examphalos and predisposition to childhood tumours [3], [6]. BWS is caused by genetic and epigenetic changes in a region of about 1 megabase on chromosome 11p15.5 encompassing some 15 genes, the majority of them being imprinted. Alterations in the imprinted expression of the IGF2 and CDKN1C genes are regarded as the key events for the

Placental overgrowth

Of particular importance for embryonic overgrowth in syndromes like BWS is the influence of imprinted gene expression in the placenta. Recent experiments suggest that placental overgrowth in BWS, caused by IGF2 overexpression and/or CDKN1C deficiency, significantly contributes to overgrowth of the embryo [15], [16]. Physiologically this may be caused by disturbing the nutritional balance between the foetus and the mother. Deregulation of other genes in the BWS region such as ASCL2

Imprinting and cancer

Imprinting defects do not only affect embryonic growth but also the inhibition of aberrant growth in later life, thereby, resulting in the development of cancer. For example, BWS is associated with a predisposition to cancer [21]. A mechanistic reason for the frequent deregulation of imprinted genes in cancer is their functional haploidy: an imprinted tumour suppressor gene may be related to increased cancer susceptibility because the inactivation of only one allele is necessary for loss of

Neurological defects in imprinting disorders

Imprinting diseases are not only associated to growth defects but appear to affect also brain functions. Neurological defects can have an influence on growth by changed hormone levels and on behaviour. The above mentioned PWS/AS are related to neurological functions: Angelman syndrome patients exhibit ataxia, hyperactivity, severe mental retardation with lack of speech, but a happy condition [4]. The phenotype appears to be caused by mutations or repression of the maternal UBE3A copy. This gene

Imprinting centres—the importance of epigenetic marks

Interestingly, imprinted genes are not evenly distributed across the genome, but are clustered. Many imprinted genes are neighboured by other imprinted genes. The clustering of imprinted genes in the genome, and also the very different types of mutations related to imprinting diseases, such as uniparental disomies, translocations in non-coding regions, and point mutations in coding sequences, suggest a regulation of imprinted genes that is based on a domain-like organisation. Detailed analysis

Imprinting switching in Prader–Willi/Angelman syndromes

The best characterised example of imprinting centres (IC) is the regulatory domain in the PWS and AS region on human chromosome 15q11-13. Frequently observed mutations in PWS are micro deletions at the first exon of the paternally expressed SNRPN whereas micro deletions 30 kb further upstream of SNRPN are associated with AS. This has led to the suggestion that these two regions encompass so-called IC that are necessary for the proper establishment and maintenance of maternal and paternal

Imprinting control in the BWS region

The human BWS region encompasses at least nine imprinted genes and is subdivided into three different subdomains: a centromeric portion that contains the maternally expressed IPL, CDKN1C and KCNQ1 genes, a central portion consisting of biallelically expressed genes and a telomeric part that contains the imprinted IGF2 and H19 genes [39]. In the mouse, the homologous region is on distal chromosome 7 and exhibits a similar order of genes [40], [41]. Two different imprinting centres have been

Local imprinting control in the mouse Igf2–H19 region

Whereas BWSIC2 influences imprinting control throughout the entire BWS region, BWSIC1 seems to regulate imprinting only in the telomeric portion that encompasses IGF2 and H19. The two genes are located in same orientation in approximately 100 kb distance to each other. IGF2 is paternally expressed, whereas H19 is expressed from the maternal allele [8], [9], [10]. Models for coordinated regulation of their imprinted expression have been gained mainly from studies in mouse. During development,

The role of non-translated RNAs

The identification of many non-translated RNAs in imprinted regions suggests a special mechanistic role of these transcripts in regulation of imprinting. So far, three different types of transcripts have been identified in human and mouse: (1) antisense transcripts that encompass long genomic regions and overlap with protein-encoding genes, such as Kcnq1ot/Kcnq1, Air/Igf2r and UBE3A-AS/UBE3A (reviewed in [30], [57]), (2) short spliced transcripts that do not overlap with protein-encoding genes

Future directions

The phenotypes of imprinting diseases are caused by deregulation of imprinted genes affecting growth, behaviour and neurological functions. Many of the basic features regulating imprinted gene expression have already been elucidated by studying human disease situations and mouse model systems. The findings already have a great impact on our general understanding of epigenetic mechanisms on gene regulation. However, a number of molecular details and general questions concerning the biological

Acknowledgements

We thank Simone Dalbert for help with the preparation of the figures, and Katrin Kremp for critical reading of the manuscript.

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Imprinting and disease

Abstract

Introduction

Section snippets

Imprinting and growth

Placental overgrowth

Imprinting and cancer

Neurological defects in imprinting disorders

Imprinting centres—the importance of epigenetic marks

Imprinting switching in Prader–Willi/Angelman syndromes

Imprinting control in the BWS region

Local imprinting control in the mouse Igf2–H19 region

The role of non-translated RNAs

Future directions

Acknowledgements

Am. J. Pathol.

Genomics

Cell

Dev. Biol.

A catalogue of imprinted genes and parent-of-origin effects in humans and animals

Hum. Mol. Genet

Beckwith–Wiedemann syndrome: imprinting in clusters revisited

J. Clin. Invest.

The impact of genomic imprinting for neurobehavioral and developmental disorders

J. Clin. Invest.

Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function

Nature

Beckwith–Wiedemann syndrome: further prenatal characterization of the condition

Am. J. Med. Genet.

IGF2 is parentally imprinted during human embryogenesis and in the Beckwith–Wiedemann syndrome

Nat. Genet.

Parental genomic imprinting of the human IGF2 gene

Nat. Genet.

Relaxation of imprinted genes in human cancer

Nature

An imprinted gene p57(KIP2) is mutated in Beckwith–Wiedemann syndrome

Nat. Genet.

Imprinting mutation in the Beckwith–Wiedemann syndrome leads to biallelic IGF2 expression through an H19-independent pathway

Hum. Mol. Genet.

Oppositely imprinted genes p57(Kip2) and Igf2 interact in a mouse model for Beckwith–Wiedemann syndrome

Genes Dev.

Epigenotype-phenotype correlations in Beckwith–Wiedemann syndrome

J. Med. Genet.

Placental-specific IGF-II is a major modulator of placental and fetal growth

Nature

p57(Kip2) regulates the proper development of labyrinthine and spongiotrophoblasts

Mol. Hum. Reprod.

Placental overgrowth in mice lacking the imprinted gene Ipl

Proc. Natl. Acad. Sci. U.S.A.

Genomic imprinting of Mash2, a mouse gene required for trophoblast development

Nat. Genet.

The human ASCL2 gene escaping genomic imprinting and its expression pattern

J. Assist. Reprod. Genet.

Roles for genomic imprinting and the zygotic genome in placental development

Proc. Natl. Acad. Sci. U.S.A.

Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS

Hum. Mol. Genet.

Multipoint analysis of human chromosome 11p15/mouse distal chromosome 7: inclusion of H19/IGF2 in the minimal WT2 region, gene specificity of H19 silencing in Wilms’ tumorigenesis and methylation hyper-dependence of H19

Hum. Mol. Genet.

Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain

Nat. Genet.

Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization

Proc. Natl. Acad. Sci. U.S.A.

Urinary odour preferences in mice

Nature

Paternally inherited HLA alleles are associated with women’s choice of male odor

Nat. Genet.

Distribution of parthenogenetic cells in the mouse brain and their influence on brain development and behavior

Proc. Natl. Acad. Sci. U.S.A.

Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mest

Nat. Genet.