The revival of DNA methylation

Current Topics in Microbiology and Immunology. Vol. 249: DNA Methylation and Cancer edited by P. A. Jones and P. K. Vogt Springer-Verlag (2000) pp. 170. ISBN 3–540-66608-7 75.50/$129.00 After a long period of relative confidentiality, the DNA methylation field has become a major research domain over the last few years. In this context, the importance of DNA methylation in human cancer has only become apparent over the last 5 to10 years. This small book (9 articles) provides a comprehensive overview of the main data and, more interestingly, presents the new concepts emerging from the recent extensive work, essentially performed over 2–3 years. The article written by B. Hendrich and A. Bird gives an overview of our current knowledge about the proteins implicated in DNA methylation, including DNA-methyltransferases and methylated-DNA-binding-proteins. It should be noted that the discovery of several of these proteins is a direct consequence of the human genome sequencing program, since they were first found ‘in silico’ by searching the databases. The specific properties of each of these partners of DNA methylation are beginning to be identified. Their implication in the regulation of histone acetylation suggests some possible mechanisms for regulation of gene expression. These models take into account, in particular, the remodeling of the chromatin structure. The value of mouse models in the understanding of the role of these proteins is discussed by P. W. Laird in another article. The present limitations of these approaches, essentially due to the non-viability of homozygous mutant mice for the main DNA-methyltransferase (Dnmt1) could be passed in the near future by the generation of conditional knockouts. Three articles by J. G. Herman and S. B. Baylin, M. F. Chan, G. Liang and P. A. Jones and J. P. Issa focus on the role of CpG island methylation in cancer and aging. These small stretches of DNA are frequently located around the transcription-start sites of approximately half of all human genes. For virtually all of these genes, with the exception of genes of the inactive X chromosome and some imprinted genes, these regions are maintained free of methylation in normal cells regardless of whether these genes are transcribed. It has been recognized that the CpG islands of a growing number of genes, either known to be involved in carcinogenesis (p16, E-cadherin, hMLH1,.) or candidate tumor supressor genes (p15, GST-Π,.) are methylated in many types of human cancer. The implication of the hypermethylation of CpG islands in tumor progression is discussed in its various aspects. In particular, the article by Chan et al. highlights the necessity to not oversimplify the relationships between methylation/inactivation and demethylation/activation. Moreover, extending his work on cancer, J. P. Issa shows that specific genes are affected by age-related methylation (EGFR, ER,.) and that such hypermethylation has disastrous consequences for the integrity of aged tissues. The article of A. P. Feinberg covers another area in this field and discusses the role of DNA methylation in imprinting and proposes a model for a role for the of loss of imprinting in cancer. Two articles investigate the action of tumor causing agents: the exogenous carcinogens and the Epstein-Barr virus (EBV). G. P. Pfeifer, M. S. Tang and M. F. Denissenko present the now well known effect of the deamination of methylcytosine on the formation of mutations. However, they insist on the finding that cytosine methylation can increase the rates of mutation by enhancing the binding of chemical carcinogens to DNA. This mechanisms is likely to have important implications for both chemical and ultra violet light induced carcinogenesis. K. D. Robertson summarize his work on the consequences of the inactivation of EBV genes on the virus' life cycle. The use of demethylating agents, like azacytidine, for reactivation of Cp-derived antigens, which could result in specific immune recognition of the tumor, is an interesting idea; however, as analyzed by M. (ABSTRACT TRUNCATED)