Genomic imprinting: employing and avoiding epigenetic processes

Abstract

Genomic imprinting refers to an epigenetic mark that distinguishes parental alleles and results in a monoallelic, parental-specific expression pattern in mammals. Few phenomena in nature depend more on epigenetic mechanisms while at the same time evading them. The alleles of imprinted genes are marked epigenetically at discrete elements termed imprinting control regions (ICRs) with their parental origin in gametes through the use of DNA methylation, at the very least. Imprinted gene expression is subsequently maintained using noncoding RNAs, histone modifications, insulators, and higher-order chromatin structure. Avoidance is manifest when imprinted genes evade the genome-wide reprogramming that occurs after fertilization and remain marked with their parental origin. This review summarizes what is known about the establishment and maintenance of imprinting marks and discusses the mechanisms of imprinting in clusters. Additionally, the evolution of imprinted gene clusters is described. While considerable information regarding epigenetic control of imprinting has been obtained recently, much remains to be learned.

Figure 1.

Components of an imprinted gene cluster. The maternal (top) and paternal (bottom) alleles of an imprinted gene cluster are depicted. Imprinted gene clusters contain maternally expressed (pink-filled boxes), paternally expressed (blue-filled boxes), and biallelically expressed genes (i.e., nonimprinted genes, green-filled boxes). These nonimprinted genes can be found in the middle of a cluster surrounded by imprinted genes. The ICR (yellow) controls imprinting of multiple genes in the region; deletion of this differentially methylated element results in loss of imprinting of the linked genes. Many imprinted clusters also contain additional DMRs (orange) that acquire DNA methylation after the preimplantation stage. Not depicted here are long ncRNAs and insulators, which have an essential role in imprinted clusters.

Figure 2.

Regulation of imprinting at the mouse H19/Igf2 locus. Shown are the maternally expressed H19 gene, which encodes a ncRNA, and the paternally expressed Igf2 gene, which encodes a fetal mitogen, with their shared enhancers (blue circles). Also shown is Ins2, which is imprinted in the yolk sac (Giddings et al. 1994). On the maternal chromosome, the unmethylated DMD/ICR binds the CTCF protein and forms an insulator, preventing the common enhancers from activating Igf2. Instead, the enhancers activate the nearby H19 promoter. On the paternal chromosome, the methylated DMD/ICR cannot bind CTCF and an insulator does not form, and, therefore, the Igf2 gene is expressed. Evidence suggests that the orthologous human locus is subject to the same regulation, although the ICR is slightly larger and contains seven CTCF-binding sites. Also depicted is DMR2, located within the Igf2 coding region, which is methylated in sperm, demethylated after fertilization, and remethylated on the paternal allele later in development. The figure is not drawn to scale.

Figure 3.

Imprinting on proximal mouse chromosome 17. Igf2r, Slc22a2, and Slc22a3 are expressed from the maternal chromosome (pink-filled boxes), and Airn is expressed from the paternal chromosome (blue arrow with blue squiggles representing RNA). Nonimprinted genes at this domain include Mas1 and Slc22a1 (green-filled boxes). The ICR (designated DMR2 in text) that serves as the promoter to Airn is shown with a yellow box. The ICR is hypermethylated on the maternal strand, preventing transcription of Airn and allowing Igf2r, Slc22a2, and Slc22a3 to be transcribed. On the paternal chromosome, the ICR is unmethylated, Airn is expressed, and surrounding genes (Igf2r, Slc22a2, and Slc22a3) are repressed (indicated with a dotted arrow). The promoter of Igf2r is a DMR (orange, designated DMR1 in text), and is methylated on the paternal allele after the initiation of imprinted gene expressed. Transcriptional activity of a given gene is indicated by arrows. The figute is not drawn to scale.