Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage.

Abstract

The agouti gene normally confers the wild-type coat color of mice. Dominant mutations at the agouti locus result in a pleiotropic syndrome that is characterized by excessive amounts of yellow pigment in the coat, obesity, a non-insulin-dependent diabetic-like condition, and the propensity to form a variety of tumors. Here, we describe a new dominant mutation at the agouti locus in which an intracisternal A-particle (IAP) has integrated in an antisense orientation immediately 5' of the first coding exon of the gene. This mutation, which we have named Aiapy, results in the ectopic expression of the agouti gene through the utilization of a cryptic promoter within the IAP 5' long terminal repeat (LTR). The coat color of Aiapy/-mice ranges from solid yellow to a pigment pattern that is similar to wild type (pseudoagouti), and the expressivity of this mutant phenotype varies with parental inheritance. Those offspring with a yellow coat ectopically express agouti mRNA at high levels and exhibit marked obesity, whereas pseudoagouti mice express agouti mRNA at a very low level and their weights do not differ from wild-type littermates. Data are presented to show that the differential expressivity of the Aiapy allele is correlated with the methylation status of the inserted IAP 5' LTR. These data further support the hypothesis that in dominant yellow mutations at the agouti locus, it is the ubiquitous expression of the wild-type agouti coding sequence that is responsible for the yellow coat color, obesity, diabetes, and tumorigenesis.

Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice

“…Transposition in hypomethylation induced tumors G Howard et al IAP elements are found in about 1000 copies per haploid genome and are normally epigenetically silenced (Boeke and Stoye, 1997). IAP transposition is documented in cultured cells (Kuff, 1990) or as germ line mutations in vivo (Michaud et al, 1994). To the best of our knowledge, this is the first example of a cancercausing IAP transposition that occurred in vivo in somatic tissue.…”

“…Ectopic expression driven by IAP promoters has been reported in the past. Different transcription start sites were reported in these cases and transcripts were found to originate from multiple sites, sometime in both sense and antisense directions (Christy and Huang, 1988;Michaud et al, 1994;Rakyan et al, 2003;Druker et al, 2004). Thus, the ectopic transcription start site may vary depending on the insertion site, the type of IAP, and possibly, the epigenetic status (for example, methylation pattern) of the inserted element.…”

Age‐ and quality‐dependent DNA methylation correlate with melanin‐based coloration in a wild bird

“…So far, only a single study has examined how DNA methylation may impact melanin coloration. This study showed that mice exhibiting a darker (pseudoagouti) phenotype have more methylated CpG sites within a intracisternal A‐particle (IAP) as well as lower levels of AsIP expression and darker coloration (Michaud et al., 1994). Our results support this earlier finding because we found no variation among individuals in DNA methylation of the MC1R but instead found variation at an antagonist ( AgRP ).…”

Expression of intracisternal A-particle retrotransposons in primary tumors of oncogene-expressing transgenic mice

“…Fulllength elements are 7.2 kb long, but internally deleted elements ± classi®ed into di erent subgroups each represented by a few hundred copies (Lueders and Mietz, 1986;Shen-Ong and Cole, 1982) ± have been identi®ed. At least some IAP elements should still be functional as transposition events can be detected, either directly (Heidmann and Heidmann, 1991) or indirectly via the mutations their transposition provoke, especially in tumor cells in culture where these elements are heavily transcribed and act as mutagenic agents (reviewed in Ku and Lueders, 1988;Ku , 1990; see also Duhl et al, 1994;Michaud et al, 1994 for germline transpositions).…”