Identification of Grf1 on mouse chromosome 9 as an imprinted gene by RLGS–M

Abstract

Normal mammalian development requires a diploid combination of both haploid parental genomes. Uniparental disomy for certain segments of specific chromosomes results in aberrant development or prenatal lethality, indicating that the parental genomes have undergone modifications during gametogenesis. These modifications result in parent-of-origin specific expression for some genes, a phenomenon called genomic imprinting. Recent work with DNA methyltransferase deficient mice showed that differential methylation is the probable basis of the imprinted character of several genes. Screening for endogenous imprinted loci using restriction landmark genomic scanning with methylation sensitive enzymes (RLGS-M) identified eight imprinted RLGS (Irigs) candidate loci. Molecular analysis of the genomic region of one of the loci (Irigs2) resulted in the discovery of the paternally imprinted U2afbp-rs gene within a previously identified imprinted region on mouse chromosome 11 (refs 5, 7). This paper describes the characterisation of a novel imprinted RLGS-M locus, Irigs3, on mouse chromosome 9 (ref. 6). Within this locus we identified the Grf1 (also called Cdc25Mm) gene, which is homologous to the RAS-specific guanine nucleotide exchange factor gene, CDC25, in Saccharomyces cerevisiae. Grf1 is located about 30 kb downstream of the methylation imprinted site, identified by RLGS-M, and shows paternal allele specific expression in mouse brain, stomach and heart. Our results indicate that imprinting may have a role in regulating mitogenic signal transduction pathways during growth and development.

DNA methylation, imprinting and cancer

“…Expression is also paternal allele-specific in neonatal brain. 14 Deletion of a repeated sequence element (40 copies of a 41-mer) 3' of the differentially methylated domain prevented establishment of paternal allele methylation in the male germ line. Methylation patterns, once disrupted at the establishment stage, never became established in the soma.…”

A catalogue of validated single nucleotide polymorphisms in bovine orthologs of mammalian imprinted genes and associations with beef production traits

“…For example, studies of the murine RASGRF1 ortholog (Rasgrf1) show that it is predominantly expressed from the paternal allele in neonatal brain tissue, with expression becoming biallelic during weaning and later into adulthood (Plass et al, 1996;Drake et al, 2009). The spatio-temporal expression patterns of this gene have led to suggestions that it may play a role in memory and learning (Giese et al, 2001).…”

Imprinted genes as potential genetic and epigenetic toxicologic targets.

“…Thus, the meiotic recombination frequencies in these regions may differ between the male and female germ cells (45). Another characteristic of imprinted genes is allele-specific cytosine methylation of CpG dinucleotides that appears to distinguish the parental alleles (46)(47)(48) by a genomewide screen termed restriction landmark genome scanning using methylation-sensitive restriction enzymes (60,63). The GABAA receptor subunit genes GABRB3, GABRA5, and GABRG3 were shown to be exclusively expressed from the paternal allele by microcell-mediated chromosome transfer (64).…”