Genomic imprinting refers to an epigenetic marking of genes that results in monoallelic expression. This parent-of-origin dependent phenomenon is a notable exception to the laws of Mendelian genetics. Imprinted genes normally function to control embryonic growth and development. They also are frequently involved in cancer because their functional haploid state makes them vulnerable to being either inactivated or overexpressed. The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) targets lysosomal enzymes to the lysosomes, and regulates the bioavailability of extracellular growth factors. It is imprinted in prenatal and postnatal mice, but postnatal M6P/IGF2R imprinting in humans is a polymorphic trait, with most individuals expressing both alleles. The M6P/IGF2R is also mutated in a number of cancers, suggesting it is a tumor suppressor. The overall hypothesis of this grant application is that M6P/IGF2R evolved as an imprinted tumor suppressor because of a parental genetic conflict in eutherian placental mammals to control fetal growth. Dr. Jirtle will test this hypothesis by determining whether: 1) M6P/IGF2R and IGF2 are imprinted in non-placental mammals; 2) M6P/IGF2R inactivation increases cancer susceptibility; 3) M6P/IGF2R biallelic expression decreases cancer susceptibility; 4) M6P/IGF2R predisposes humans to cancer because of either inherited polymorphisms or postnatal imprinting; and 5) M6P/IGF2R mutation is a common early oncogenic event that is independent of ethnic origin. The proposed studies will determine if mammalian cancer susceptibility is a detrimental result of genomic imprinting evolution.
| Dolinoy, Dana C; Weidman, Jennifer R; Jirtle, Randy L (2007) Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol 23:297-307 |
| Waterland, Robert A; Lin, Juan-Ru; Smith, Charlotte A et al. (2006) Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum Mol Genet 15:705-16 |
| Weidman, Jennifer R; Dolinoy, Dana C; Maloney, Kristin A et al. (2006) Imprinting of opossum Igf2r in the absence of differential methylation and air. Epigenetics 1:49-54 |
| Weidman, Jennifer R; Maloney, Kristin A; Jirtle, Randy L (2006) Comparative phylogenetic analysis reveals multiple non-imprinted isoforms of opossum Dlk1. Mamm Genome 17:157-67 |
| Murphy, Susan K; Nolan, Catherine M; Huang, Zhiqing et al. (2006) Callipyge mutation affects gene expression in cis: a potential role for chromatin structure. Genome Res 16:340-6 |
| Luedi, Philippe P; Hartemink, Alexander J; Jirtle, Randy L (2005) Genome-wide prediction of imprinted murine genes. Genome Res 15:875-84 |
| Murphy, Susan K; Freking, Brad A; Smith, Timothy P L et al. (2005) Abnormal postnatal maintenance of elevated DLK1 transcript levels in callipyge sheep. Mamm Genome 16:171-83 |
| Evans, Heather K; Weidman, Jennifer R; Cowley, Dale O et al. (2005) Comparative phylogenetic analysis of blcap/nnat reveals eutherian-specific imprinted gene. Mol Biol Evol 22:1740-8 |
| Jirtle, Randy L (2004) IGF2 loss of imprinting: a potential heritable risk factor for colorectal cancer. Gastroenterology 126:1190-3 |
| Weidman, Jennifer R; Murphy, Susan K; Nolan, Catherine M et al. (2004) Phylogenetic footprint analysis of IGF2 in extant mammals. Genome Res 14:1726-32 |
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