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Clarification of mechanisms how aberrant DNA methylation is induced
Humans are exposed to various endogenous and exogenous carcinogenic factors in daily life. These factors include mutagens, such as radiation and some chemicals, and promoters, such as tissue injury. In addition to these, factors that induce aberrant DNA methylation are also likely to be carcinogenic factors (Fig. ) (Ushijima and Okochi-Takada, 2005 , Hattori and Ushijima, 2016 ).
Fig. Inducing factors for abnormality of DNA methylation
Aging has been known to induce aberrant DNA methylation for more than a decade. Ulcerative colitis and hepatitis virus infections are also known to induce aberrant DNA methylation. We demonstrated that Helicobacter pylori (H. pylori) infection, an important cause of human gastric cancer, is a strong inducer of aberrant DNA methylation (Maekita et al., 2006 ). We also found that some genes are methylated in association with the duration of smoking history (Oka et al., 2009 ). We are currently developing detection systems for chemicals that induce aberrant DNA methylation and demethylation, of which some drugs are already reported to be capable . We also showed that aberrant DNA methylation can be increased due to intrinsic abnormality in a cell (Ushijima et al., 2005 ).
DNA methylation itself is not harmful and is physiologically present in a cell at an appropriate level. As a factor that induces an abnormal decrease of DNA methylation, deficiency of S-adenosyl-L-methionine (SAM), a methyl group donor, is known. This has been demonstrated mainly using animals that were exposed to deficiency or over-intake of dietary factors involved in synthesis of SAM.
It is also important to reveal what kinds of genes are targets of induction of aberrant DNA methylation. We found that there is a specificity in target genes of aberrant DNA methylation induction, and clarified molecular mechanisms involved in the specificity (Takeshima et al., 2009 , Takeshima et al., 2011 , Takeshima and Ushijima, 2010 )