[HTML][HTML] Beckwith-Wiedemann syndrome: imprinting in clusters revisited

ER Maher, W Reik - The Journal of clinical investigation, 2000 - Am Soc Clin Investig
The Journal of clinical investigation, 2000Am Soc Clin Investig
Genomic imprinting, a process that causes genes to be expressed according to their
parental origin, affects a minority of human genes, probably less than 1,000. Nevertheless,
this class of epigenetic modification acts on many genes with critical roles in growth and
development, and disordered imprinting is implicated in genetic disease and in many
cancers. Various theories have been proposed to explain the evolution of imprinting in
mammals. The most popular is the Haig parental conflict model, which holds that imprinting …
Genomic imprinting, a process that causes genes to be expressed according to their parental origin, affects a minority of human genes, probably less than 1,000. Nevertheless, this class of epigenetic modification acts on many genes with critical roles in growth and development, and disordered imprinting is implicated in genetic disease and in many cancers. Various theories have been proposed to explain the evolution of imprinting in mammals. The most popular is the Haig parental conflict model, which holds that imprinting evolved as a result of opposing interests of the maternal and paternal genomes. Thus, in polygamous species, paternally derived genes will favor fetal growth at the expense of depleting maternal resources and disadvantaging further offspring. In contrast, the maternal genes will oppose the paternal effect and conserve resources to ensure the fitness of the mother and future offspring. This model predicts that although paternally expressed imprinted genes should promote growth, maternally expressed genes should have opposite effects. Many, but not all, imprinted genes identified to date conform to these predictions (1). The mechanisms by which imprinting is established and maintained are the subject of intense investigation (2). The process must involve a reversible epigenetic marking, and a number of features of imprinted genes have been described. Thus, differential methylation of maternal and paternal alleles is a major characteristic of imprinted genes, and defects in methylation processes (eg, methyltransferase deficiency) disrupt normal genomic imprinting. Parental allele-specific alterations in the chromosome environment of imprinted genes are revealed by the presence of asynchronous DNA replication and differences in chromatin structure and modification (eg, histone acetylation). A striking feature of imprinted genes in mammals is their tendency to cluster in the genome. The arrangement of coordinately or oppositely imprinted genes within a cluster offers insights into the mechanisms by which cells establish and maintain appropriate imprints on functionally related genes. Here, we discuss the organization and function of a major imprinted gene cluster, occurring on human chromosome 11p15. 5, that has been implicated in the imprinting disorder Beckwith-Wiedemann syndrome (BWS) and in a variety of human cancers including Wilms’ tumor (3, 4).
Because the regulation of imprinted genes in the homologous region in the mouse (distal region of chromosome 7) is broadly conserved between mice and humans, experiments in mice have complemented molecular analyses of BWS pathology and have contributed greatly to our current knowledge of mammalian genomic imprinting mechanisms. In this review, we consider the mechanisms and role of genomic imprinting in human development and in BWS pathogenesis, drawing on research on the human and the mouse clusters of imprinted genes.
The Journal of Clinical Investigation