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Cancer has long been viewed as a genetic disease; however, epigenetic silencing as the result of aberrant promoter DNA methylation is frequently associated with cancer development, suggesting an epigenetic component to the disease. Nonetheless, it has remained unclear whether an epimutation (an aberrant change in epigenetic regulation) can induce tumorigenesis. Here, we exploited a functionally validated cis-acting regulatory element and devised a strategy to induce developmentally regulated genomic targeting of DNA methylation. We used this system to target DNA methylation within the p16(Ink4a) promoter in mice in vivo. Engineered p16(Ink4a) promoter hypermethylation led to transcriptional suppression in somatic tissues during aging and increased the incidence of spontaneous cancers in these mice. Further, mice carrying a germline p16(Ink4a) mutation in one allele and a somatic epimutation in the other had accelerated tumor onset and substantially shortened tumor-free survival. Taken together, these results provide direct functional evidence that p16(Ink4a) epimutation drives tumor formation and malignant progression and validate a targeted methylation approach to epigenetic engineering.

Cancer has long been viewed as a genetic disease; however, epigenetic silencing as the result of aberrant promoter DNA methylation is frequently associated with cancer development, suggesting an epigenetic component to the disease. Nonetheless, it has remained unclear whether an epimutation (an aberrant change in epigenetic regulation) can induce tumorigenesis. Here, we exploited a functionally validated cis-acting regulatory element and devised a strategy to induce developmentally regulated genomic targeting of DNA methylation. We used this system to target DNA methylation within the p16Ink4a promoter in mice in vivo. Engineered p16Ink4a promoter hypermethylation led to transcriptional suppression in somatic tissues during aging and increased the incidence of spontaneous cancers in these mice. Further, mice carrying a germline p16Ink4a mutation in one allele and a somatic epimutation in the other had accelerated tumor onset and substantially shortened tumor-free survival. Taken together, these results provide direct functional evidence that p16Ink4a epimutation drives tumor formation and malignant progression and validate a targeted methylation approach to epigenetic engineering. [ABSTRACT FROM AUTHOR]

The article discusses a study on why epigenetic regulation alters among individuals and how environmental factors modify the risk for common diseases among individuals. It provides an extensive epigenomic analysis of monozygous (MZ) twins which concludes that the differences of epigenetic among MZ twins arise in older MZ twins that are related to the epigenetic changes and environmental differences accumulated with aging. The study shows that the epigenetic dysregulation could cause developmental cancer and diseases. However, it says that the role played by epigenetics in the pathogenesis of the chronic diet-related diseases including cardiovascular disease, obesity, and type-2 diabetes is not yet clear.