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'Hot off the press' is a daily listing of the most recent articles in epigenetics and imprinting

p16 Epimutation Causes Cancer

14 March 2015: Hypermethylation of the promoter region of p16 causes cancer and reduces survival in mice according to a recent report by Lanlan Shen and her colleagues in The Journal of Clinical Investigation.

The history of p16 as a human tumor suppressor gene is complex. Only months after gene deletion evidence from a variety of tumor cell lines indicated the involvement of p16 in the genesis of cancer (Nobori et al. 1994; Kamb et al. 1994), its tumor suppressor function was brought into question (Spruck et al. 1994; Cairns et al. 1994).

According to the two-hit theory of carcinogenesis by Knudson (Knudson 1971), a tumor suppressor is characterized by both copies of the gene being inactivated genetically, thereby eliminating its growth inhibition. Thus, tumors with loss of heterozygosity (LOH) at 9p21 - the chromosomal location of p16 - should have a high frequency of intragenic mutations in the other allele that block gene function. In contrast to this prediction, primary tumors with LOH at the p16 locus had a paucity of mutations in the remaining allele (Spruck et al. 1994; Cairns et al. 1994).

This conundrum appeared to be resolved in 1995 by the finding that p16 function is often inactivated in tumors by promoter hypermethylation (Merlo et al. 1995). Nevertheless, there has always been the nagging question: Does tumor hypermethylation at the p16 locus cause or result from cancer formation? This critically important question has now been answered twenty years later by an elegant set of experiments. By using a strategy to target DNA methylation directly to the p16 promoter in mice, epigenetic inactivation of p16 function has been demonstrated unequivocally to cause tumor formation (Yu et al. 2015).

Antagonistic Growth Promoting Effects of Imprinted Genes

Imprinted genes are monoallelic expressed in a parent-of-origin dependent manner (Jirtle and Weidman 2007).The conflict theory of genomic imprinting predicts that maternally expressed genes are antigrowth while paternally expressed genes are progrowth (Haig and Graham 1991). The first two genes experimentally identified to be imprinted, the maternally expressed Igf2r (Barlow et al. 1991) and the paternally expressed Igf2 (DeChiara et al. 1991), were shown over two decades ago to adhere to this prediction. A second set of oppositely imprinted, fetal growth antagonistic genes has now been identified, the maternally expressed [Grb10](http://omim.org/entry/601523 Read more...

Autism and Schizophrenia: The Antithesis of Each Other?

Genomic imprinting is a phenomenon where one parental allele is silenced epigenetically, resulting in monoallelic parent-of-origin gene expression (Jirtle and Weidman 2007). It evolved about 150 million years ago with the advent of viviparity and placentation in a common ancestor to Therian mammals (i.e. Marsupials and Eutherians) (Killian et al. 2000). Badcock and Crespi postulated in their imprinted brain theory that autism spectrum disorders (AS) and schizophrenia spectrum (SS) disorders are the antithesis of each other, and result from the skewing of paternally and maternally imprinted gene expression in the brain during development. Paternally expressed imprinted genes tend to be progrowth, and those that are maternally expressed antigrowth. Read more...

Environmental Epigenomics in Health and Disease

Springer has recently published two books on environmental epigenomics that are edited by Randy L. Jirtle and Frederick L. Tyson -- Epigenetics and Disease Origins and Epigenetics and Complex Diseases. The overall purpose of these books is to give readers an overview of how environmental exposures can influence the risk of disease in adulthood by disrupting epigenetic processes and reprogramming during early development. Read more...

Radiation Epigenetics

Humans are exposed to low-dose ionizing radiation (LDIR) from a number of environmental and medical sources. In addition to inducing genetic mutations, there is concern that LDIR may also alter the epigenome. Such heritable effects early in life can either be positively adaptive or result in the enhanced formation of diseases, including cancer, diabetes, and obesity. In this study, we show that LDIR significantly increases DNA methylation at the viable yellow agouti (Avy) locus in a dose- and sex-dependent manner. Moreover, maternal dietary antioxidant supplementation mitigated both the DNA methylation changes and coat color shift in the irradiated offspring. Thus, LDIR exposure during gestation elicits epigenetic alterations that lead to positive adaptive phenotypic changes that are negated with antioxidants, indicating they are mediated in part by oxidative stress. Read more...

These Little Piggies!

Imprinted genes are monnoallelically expressed in a parent-of-origin dependent manner because the same parental allele is always epigenetically silenced (Jirtle and Weidman 2007). The phenomenon of genomic imprinting evolved in mammals around 200 million years ago in a common ancestor to marsupials and eutherians (Killian et al. 2000). Once this unique epigenetic form of gene regulation evolved, natural selection may have utilized the resulting marked variation in gene expression to drive mammalian speciation, providing a plausible explanation for why mammalian species vary markedly in their imprinted gene repertoires. Read more...