Randy Jirtle

..These major deficits in knowledge markedly impair our ability to understand fully the etiology of cancer and the importance of the epigenome in diagnosing and preventing this devastating disease...

..The primary objective is to estimate the proportion of women taking folic acid (FA) doses exceeding the TUL before and during pregnancy, and to identify correlates of high FA use...

..The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis...

..Methods are now becoming available to investigate the relevance of these phenomena to human disease...

..To report the incidence of late complications in long-term survivors of very-high-dose thoracic radiotherapy (RT) treated on a prospective clinical trial...

..5002G > A genotype and EGA was not evident. These findings suggest that nonsynonymous polymorphisms in M6P/IGF2R may contribute to the risks of EGA and noncardia adenocarcinomas. Larger studies are required to confirm these findings...

..These findings suggest that dietary supplementation, long presumed to be purely beneficial, may have unintended deleterious influences on the establishment of epigenetic gene regulation in humans...

....

..Thus, the regulatory mechanisms of Igf2r imprinting did not evolve convergently within the Therian subclass of mammals...

..Such comparative studies will also further our understanding of the molecular evolution and phylogenetic distribution of imprinted genes...

....

....

..9% higher methylation at the PLAGL1 DMR compared with normal birth weight infants. Our findings confirm that severe maternal depressed mood in pregnancy is associated with LBW, and that MEG3 and IGF2 plasticity may play important roles...

....

..Thus, we present compelling evidence that early developmental exposure to BPA can change offspring phenotype by stably altering the epigenome, an effect that can be counteracted by maternal dietary supplements...

..Loss of heterozygosity in dysplastic liver nodules provides additional evidence that M6P/IGF2R haploid insufficiency is an early event in human hepatocarcinogenesis...

....

..Our findings demonstrate that DNA sequence characteristics, including recombination hot spots, are sufficient to accurately predict the imprinting status of individual genes in the human genome...

..This review discusses the evolution of imprinting in Therian mammals, and the importance of imprinted genes in human health and disease...

..This finding also suggests that the complexity of imprinting regulation observed at other loci may, in part, be directly related to the amount of time they have been imprinted...

..Thus, we provide the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome...

..These findings clearly demonstrate that imprinted genes did not all evolve before the divergence of marsupials and eutherians...

..They suggest that the effect of the callipyge mutation is to interfere with the normal postnatal downregulation of DLK1 expression...

..We propose a model incorporating these results that can also account for the enigmatic normal phenotype of homozygous mutant sheep...

..We observe that the number, type, and relative orientation of repeated elements flanking a gene are particularly important in predicting whether a gene is imprinted...

..To investigate the relationship between loss of heterozygosity (LOH) for mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) and the outcomes for primary HCC patients treated with partial hepatectomy...

..Of interest, PEG1-AS was expressed predominantly in testis and in mature motile spermatozoa, indicating a possible role for this transcript in human sperm physiology and fertilization...

..These results indicate that post-weaning diet can permanently affect expression of Igf2, suggesting that childhood diet could contribute to IGF2 LOI in humans...

..Our study establishes zebrafish as a novel, genetically tractable model for in vivo studies of MPR function and lysosome biogenesis...

..A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation...

..Initial functional analysis indicates sequence encompassing the mutation is part of a novel transcript expressed in sheep fetal muscle we have named CLPG1...

..They will also be helpful in determining under what circumstances the mouse is an appropriate toxicological model for assessing human risk from agents that elicit their biological effect primarily by altering the epigenome. ..

..Finally, for Aim 4 studies, a transgenic mouse will be constructed with inducible knock-out of the M6P/IGF2r gene for evaluation in the carcinogenesis models. ..

..The proposed studies will determine if mammalian cancer susceptibility is a detrimental result of genomic imprinting evolution. ..

..They will also be helpful in determining under what circumstances the mouse is an appropriate toxicological model for assessing human risk from agents that elicit their biological effect primarily by altering the epigenome. ..

..abstract_text> ..

....

..The results of these studies should provide a better understanding of the role of the M6P/IGFII receptor and TGFbeta in liver tumor promotion, and enable us to assess substances for human carcinogenic risk with greater accuracy. ..

....

..alpha1-adrenergic co-mitogenic activities). In summary, we will investigate at the cellular, biochemical, and molecular levels the mechanisms by which PB promotes hepatocellular tumor formation...

..In summary, we will utilize hepatocyte transplantation, primary culture and molecular biological techniques to investigate at the organismal, cellular and molecular level the mechanism(s) of hepatocellular tumor formation with PB...