Imprinting is a mammalian adaptation whereby subsets of genes are differentially expressed depending on their parental origin; this monoallelic expression is maintained by DNA methylation. Loss of imprinting (LOI) is a common feature of many human tumors, yet whether LOI directly promotes tumorigenesis or is merely a consequence of epigenetic deregulation in transformed cells is unclear. To directly examine the function of LOI in tumorigenesis, we developed a model for LOI using conditional inactivation and reactivation of the DNA methyltransferase Dnmt1 to generate imprint-free mouse embryonic stem cells (IF-ES cells). IF- embryonic fibroblasts (IF-MEFs) derived from these ES cells display an increased growth rate, cellular immortality, resistance to growth inhibition by TGFb and form tumors when injected into SCID mice. Somatic contribution of IF-ES cells in chimeric animals leads to tumor formation by 12 months of age, causing hepatocellular carcinoma, intestinal adenomas, and a range of other primary cancers derived from the IF-ES cells. Our data are consistent with global LOI in embryonic stem cells having a causal role in tumor formation in adults. This finding demonstrates the importance of imprinting as a tumor suppressor mechanism and identifies a pathway by which immortality conferred by LOI lowers the threshold for transformation.
Loss of Imprinting