Genomic imprinting of the human IGF2R/CIMPR gene

Genomic imprinting is an epigenetic mechanism that silences one of the two parental alleles in a diploid cell thereby reducing expression levels by 50%. Epigenetic mechanisms operate via modifications to DNA or chromatin and are reversible. The IGF2R/CIMPR (insulin like growth factor type 2 receptor also known as the cation- independent mannose 6-phosphate receptor) is a multifunctional transport receptor that has been identified as a tumor suppressor gene which likely functions by changing concentrations of active growth regulators and the integrity of the extracellular matrix. The mouse Igf2r/Cimpr gene shows widespread imprinted maternal-specific expression in embryos and adults. In contrast, the human IGF2R/CIMPR gene only shows maternal-specific expression in embryo/fetal stages and then only in some individuals. So far, all tested adult human tissues lack imprinted IGF2R/CIMPR expression. IGF2R/CIMPR was also found to show imprinted expression in both normal kidney and tumor tissue from Wilm`s tumor patients that lack an apparent genetic change at this locus. However, the imprinted status of this gene is still a matter of controversy. Genetic changes in the IGF2R/CIMPR locus that include loss of heterozygosity with coding mutations in the retained allele have been identified in breast and hepatocellular cancers, and coding mutations seen in mismatch repair defective tumors. This data indicates that that genetic mutations reduce IGF2R/CIMPR expression in tumors. If the IGF2R/CIMPR is imprinted the possibility exists that epigentic changes could also reduce expression in tumors. This project aims (i) to investigate the imprinted status of the human IGF2R/CIMPR gene, in particular, we aim to test the hypothesis that imprinted expression of the human IGF2R/CIMPR gene can be induced by the same epigentic mechanism as used in the mouse. (ii) to develop molecular probes that will be used to test the imprinted expression of IGF2R/CIMPR in tissues and in single cells. (iii) to use these tools to test more fully the imprinted status of IGF2R/CIMPR in human tumors and in normal human tissue.