Paternal and maternal genomes confer opposite effects on proliferation, cell-cycle length, senescence, and tumor formation

Abstract

Loss of imprinting is the silencing of active imprinted genes or the activation of silent imprinted genes, and it is one of the most common epigenetic changes associated with the development of a wide variety of tumors. Here, we have analyzed the effects that global imprinted gene expression has on cell proliferation and transformation. Primary mouse embryonic fibroblasts (MEFs), whose entire genome is either exclusively paternal (androgenetic) or maternal (parthenogenetic), exhibit dramatically contrasting patterns of growth. In comparison with biparental MEFs, androgenetic proliferation is characterized by a shorter cell cycle, increased saturation density, spontaneous transformation, and formation of tumors at low passage number. Parthenogenetic MEFs reach a lower saturation density, senesce, and die. The maternally expressed imprinted genes p57 kip2 and M6P͞Igf2r retard proliferation and reduce the long-term growth of MEFs. In contrast, the paternally expressed growth factor Igf2 is essential for the longterm proliferation of all genotypes. Increased Igf2 expression in primary MEFs not only stimulates proliferation, but also results in their rapid conversion to malignancy with tumor formation of short latency. Our results reveal that paternally expressed imprinted genes, in the absence of maternal imprinted genes, predispose fibroblasts to rapid transformation. A potent factor in their transformation is IGF2, which on increased expression results in the rapid conversion of primary cells to malignancy. These results reveal a route by which malignant choriocarcinoma may arise from molar pregnancies. They also suggest that the derivation of stem cells from parthenogenetic embryos, for the purposes of therapeutic cloning, may be ineffective.genomic imprinting ͉ uniparental ͉ Igf2 ͉ p57 kip2 ͉ cloning

Inactivation of Dnmt3b in Mouse Embryonic Fibroblasts Results in DNA Hypomethylation, Chromosomal Instability, and Spontaneous Immortalization

“…"Androgenetic" MEFs, which contain two copies of the paternal genome, are prone to spontaneous immortalization and transformation, whereas "parthenogenetic" MEFs, which contain two copies of the maternal genome, undergo premature senescence and apoptosis. These effects have been attributed to loss of imprinting (22). Whereas a clear role for Dnmt3b in the maintenance of genomic imprinting has yet to be determined, it is possible that abnormal expression of imprinted genes, due to DNA demethylation, might determine whether Dnmt3b-deficient MEF cells would undergo spontaneous immortalization or premature senescence.…”

Evolutionary biology of cancer

“…Losses and gains of genomic imprinting are strongly associated with cancer [54], owing to the functional haploidy of imprinted genes and their roles in control over cellular resources during development [49]. These studies suggest that conflicts over control of cellular resources often lead to the evolution of genetic and epigenetic systems [54,55] that increase cancer risk.…”

“…Comparative viewpoints on cancer also lead directly to concerns that animal models, such as mice, have less applicability to humans than is currently believed, because anticancer adaptations should be more or less unique to each species [60] and artificial selection inadvertently applied to laboratory animals has fundamentally altered their physiology and life history [41,84]. cancer from computer to laboratory to clinic (Box 3), analyses of how cancer evolves should also provide novel insights into outstanding questions in evolutionary ecology [43,47,48,55,63,66]. Only through integrated molecular, ecological and evolutionary analyses of cancer, at the somatic, population and macroevolutionary levels, will we come to understand and govern this unique disease.…”

Derivation of human embryonic stem cell lines from parthenogenetic blastocysts

“…For patients with Parkinson's or other neurodegenerative disorders (especially in female patients), there may be hope for autologous and personalized stem cell treatments of the otherwise devastating diseases. However, one report has suggested that the loss of epigenetic imprinting may limit the effectiveness of stem cells derived from parthenogenetic embryos [12]. As paternally imprinted genes were shown to be stable in androgenetic (two paternal chromosome sets) stem cells [13], maternal factors seem to have a major effect on the instability of imprinted genes [14].…”