Genomic Imprinting and Modifier Genes in the Mouse

Abstract

Imprinted genes provide an excellent experimental system to examine the epigenetic control of gene expression. This is, first, because an active and inactive allele of the same gene are present in the same cell, so that the differentiation between expressed and nonexpressed status involves cis-acting genetic elements, and, second, because there must exist a long-lasting memory of the origin of alleles (from sperm or egg) that is sustained through numerous rounds of replication. Here we examine the epigenetic features of the imprinted insulin-like growth factor 2 (Igf2) gene and postulate that some of the methylation and chromatin features in this gene are influenced or controlled by methylation and chromatin modifier genes. In the second part of the chapter, we describe a genetic system for the identification and potential isolation of such modifiers of methylation and chromatin.

In mouse and human, the Igf2 gene is almost exclusively expressed from the paternal chromosome (DeChiara et al. 1991; Giannoukakis et al. 1993; Ohlsson et al. 1993). For a number of reasons, this particular gene is important for the study of mechanisms and consequences of imprinting. First, Igf2 has a very strong effect on fetal growth, one of the key phenotypes controlled by imprinted genes. Second, there are at least two other (maternally expressed) imprinted genes, Igf2r and H19, that interact with the Igf2 pathway (Wang et al. 1994; Leighton et al. 1995a). Third, the Igf2 region of imprinted genes is implicated in a number of human diseases, most notably the fetal overgrowth and...