Genomic imprinting-an epigenetic gene-regulatory model

Abstract

Epigenetic mechanisms (Box 1) are considered to play major gene-regulatory roles in development, differentiation and disease. However, the relative importance of epigenetics in defining the mammalian transcriptome in normal and disease states is unknown. The mammalian genome contains only a few model systems where epigenetic gene regulation has been shown to play a major role in transcriptional control. These model systems are important not only to investigate the biological function of known epigenetic modifications but also to identify new and unexpected epigenetic mechanisms in the mammalian genome. Here we review recent progress in understanding how epigenetic mechanisms control imprinted gene expression.

Figure 1

Bypassing paternal imprints to generate bi-maternal mice. On mouse chromosome 7, a paternal DNA methylation imprint (Me/blue circle) represses the ICE and allows expression of Igf2 from the paternal chromosome in normal diploid embryonic cells (arrow). Igf2 is not expressed from a maternal chromosome that has an active unmethylated ICE (lollipop). A similar but opposite situation occurs in a neighboring imprinted cluster on this chromosome, where expression of Cdkn1c depends on a maternally methylated ICE (Me/red circle). Note that chromosome 7 contains only one of the two normally paternally methylated ICEs deleted to generate bi-maternal mice [7••]. DNA methylation imprints on ICEs are erased in primordial germ cells of the developing gonad and in females these imprints are reacquired during oocyte maturation. Chromosomes in immature oocytes lack maternal ICE imprints and, if they also genetically lack Pat-ICEs (oblique rectangle) that are normally modified by paternal gametic DNA methylation, then this haploid chromosome set will have a maternal origin with the imprinted expression pattern of the paternal genome [7••].

Figure 2

The unmethylated ICE is a cis-acting repressor. Three examples of how the unmethylated ICE can repress mRNA genes in cis are known. (a) The unmethylated ICE in the mouse Igf2 cluster on chromosome 7 forms an insulator on the maternal chromosome by binding CTCF and COHESIN (COH) proteins, which blocks the access of Igf2 to enhancers located downstream to the H19 ncRNA [8,12••]. (b) The unmethylated ICE in the mouse Igf2r imprinted gene cluster on chromosome 17 (top) and in the mouse Kcnq1 imprinted gene cluster on chromosome 7 (bottom) contains an active promoter, respectively, for the Airn and Kcnq1ot1 macro ncRNAs. Both these ncRNAs repress multiple genes in cis on the paternal chromosome [13,14,15•]. (c) The unmethylated ICE in the mouse H13 (Minor histocompatibility antigen H13 encoding a signal-peptide peptidase) imprinted cluster on chromosome 2 contains the active promoter for the Mcts2 retrogene, and either the unmethylated ICE or Mcts2 expression induces premature polyadenylation of H13 transcripts that lack enzyme activity [16••]. The maps are not drawn to scale and show imprinted expression in the visceral yolk sac (A), for placenta (B) and in adult brain (C); genes showing bi-allelic expression are not indicated. Arrow: expressed gene, Double-headed arrow: expressed ncRNA or retrogene, lollipop: silent gene, Me/blue circle: paternal gametic methylation imprint, Me/red circle: maternal gametic methylation imprint.