Noncoding RNAs at H19/IGF2 Locus: Role in Imprinting, Gene Expression, and Associated Pathologies

Abstract

Genomic imprinting is a form of epigenetic regulation whereby some genes are silenced according to their parental origin. The H19/IGF2 locus located in the chromosome 11 in p15.5 is the best characterized imprinted cluster. The locus generates two types of noncoding RNAs: the mRNA-like noncoding RNA H19 and the antisense RNA 91H. The regulation of H19 and its closely linked and reciprocally imprinted neighbor, IGF2, has been studied intensively both as a model for understanding imprinting control mechanisms and because of its role in human diseases. As with all imprinted clusters, H19 imprinted expression is regulated by an Imprinting Control Region (ICR), which controls interactions between promoters and shared enhancers. The locus functions like an “insulator model” in which trans-factors and epigenetic modifications are also required for full expression of genes. It is well assumed that H19 RNA functions as a riboregulator of which, expression is developmentally regulated. Elsewhere, the antisense RNA 91H has been recently discovered as a large and maternally imprinted noncoding RNA. It plays a role in the paternal IGF2 regulation and is overexpressed in breast cancer. This original trans-effect may be due to 91H participation in the three-dimensional organization of the locus, essential for the appropriate expression of genes. In this chapter, we summarize our current understanding of the molecular and biological roles of the ncRNAs expressed at the H19/IGF2 domain, both in terms of their contribution to genomic imprinting control, as well as in terms of cellular targets they might interact with. We also review knowledge of the locus-associated pathologies such as cancers and children syndromes.