Mammalian genomic imprinting

Abstract

Normal mammalian development requires a maternal and paternal contribution, which is attributed to imprinted genes, or genes that are expressed from a single parental allele. Approximately 100 imprinted genes have been reported in mammals thus far. Imprinted genes are controlled by cis-acting regulatory elements, termed imprinting control regions (ICRs), which have parental-specific epigenetic modifications, including DNA methylation. ICRs are methylated by de novo DNA methyltransferases during germline development; these parental-specific modifications must be maintained following fertilization when the genome is extensively reprogrammed. Many imprinted genes reside in ∼1-megabase clusters, with two major mechanisms of imprinting regulation currently recognized, CTCF-dependent insulators and long noncoding RNAs. Unclustered imprinted genes are generally regulated by germline-derived differential promoter methylation. Here, we describe the identification and functions of imprinted genes, cis-acting control sequences, trans-acting factors, and imprinting mechanisms in clusters. Finally, we define questions that require more extensive research.

Figure 1.

Imprinted genes are expressed in a parental-origin-specific manner. In the center, a cell is depicted with a chromosome inherited maternally (red) or paternally (blue), and two imprinted genes. Gene A is transcribed from the maternal allele (green box and arrow indicating transcription) and repressed on the paternal allele (light blue box). In contrast, gene B is transcribed from the paternal allele (green box and arrow) and repressed on the maternal allele (light pink box). Uniparental embryos and embryos that are uniparental for a given chromosome have been used to show that imprinted genes are critical for development as well as to identify imprinted genes (see text).

Figure 2.

DNA methylation is essential for establishment and maintenance of imprinting. Shown are the two types of DNA methylation present at imprinted loci. (A) Greater than 16 imprinted loci are associated with maternal-specific methylation. For these loci, DNA methylation (filled lollipops) is associated with the promoter of a repressed gene, whereas hypomethylation (gray lollipops) is associated with the promoter of the expressed gene (arrow). (B) Four imprinted loci are associated with DNA methylation in intergenic regions. In one case (H19 and Igf2), the DNA methylation regulates a CTCF-dependent insulator element (see text).

Figure 3.

Cycle of Imprinting. Imprints are acquired in a sex-specific manner in the germline: Maternally and paternally DNA methylated ICRs gain DNA methylation in oocytes and sperm, respectively. Imprints are maintained despite reprogramming and global changes in DNA methylation after fertilization. Paternal imprints are resistant to the active demethylation of the paternal genome in the zygote, and maternal methylation of ICRs is retained despite passive maternal demethylation in the preimplantation embryo. De novo DNA methylation of the genome begins at the end of the preimplantation stage of development. Imprints are maintained in somatic cells throughout the lifetime of the organism. In the germline, DNA methylation is erased during migration of PGCs into the genital ridge. Imprints are then reestablished appropriately during gametogenesis for transmission to the next generation.