DNA methylation patterns

Sokol RZ Health Research Association, Inc., Los Angeles, CA Pb exposure in utero may induce an inherited change in DNA methylation patterns in Pb exposed pups, the mechanism by which Pb exposure during the critical time of sexual differentiation induces reproductive axis abnormalities in adulthood National Institute of Environmental Health Sciences... 

Bird, A. (2002) DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6-21. 

DNA methylation patterns are heritably propagated in somatic lineage cells, but in some circumstances methylation of DNA is a dynamic process, especially during early embryogenesis. Remodeling of DNA methylation levels and patterns have been observed during development of many vertebrate species [5 9], the most dramatic example being the rapid demethylation of the mouse sperm DNA few... 

Collectively, the results of these studies suggest a dominant role for DNA methylation, which dictates the acetylation status of the histones, and thereby, chromatin structure (Fig. 5c). The cells jealously preserve and inherit DNA methylation patterns, and respectively chromatin conformation, through mitosis. 

Fruhwald MC. DNA methylation patterns in cancer novel prognostic indicators . Am J Pharmacogenomics 2003 3 245-260. 

Fig. 9.11 In the DNA of vertebrates, a proportion of the cytosines in the CG sequence are methylated. The DNA methylation pattern is faithfully maintained in the course of embryogenesis and cell differentiation, because normally the discriminating, selective action of the methyltransferase maintains the pattern of DNA methylation. once it is established. Not so in imprinted genes, for which the lack of a methylating enzyme is thought to be responsible. (This information is from ref. 42. Rg. 9-68. p. 450 and is shown with permission of Taylor and Francis. Inc.)...

There are otho- carcinogenic processes that do not involve direct DNA reactivity, but either facilitate DNA damage or cause increased cell proliferation (and thereby increase potential for propagation of DNA damage) indirectly. These mechanisms include inhibition of DNA repair, alteration of DNA methylation patterns, oxidative damage, and modulation of signal transduction pathways, among others (Pratt and Barron 2003). Involvement of these mechanisms as part of the MOA is likely be associated with tumor development that has a nonlinear dose response howevCT, because it is frequently difficult to establish a precise MOA for these processes, linear extrapolation is often invoked as a default assumption. 

A characteristic distribution pattern of 5-methyl cytidine (m5C) is found within each cell, which remains intact upon cell division. Mechanisms must therefore exist to ensure that the methylation pattern is precisely retained in the daughter cells following cell division. The enzymes responsible for DNA methylation at CpG sequences are the DNA methyltransferases. The methyl group is derived from S-adenosyl methionine. Several DNA methyltransferases have been characterized, some of which, e.g., Dnmtl, can perform hemi-methylation in the CpG sequences (Fig. 1.38). The preferential substrates for hemi-methylation are DNA sequences in which the complementary strand is already methylated. Such a hemi-methylation occurs, for example, shortly after replication of the sequence. This type of DNA methylation is also called maintenance methylation and is responsible for the inheritance of the methylation pattern. In addition to maintenance methylation, de novo methylation at CpG sequences is also possible. An important inhibitor of DNA methyltransferases is 5-aza-cytidine, which blocks DNA methylation leading to a change in DNA methylation patterns of cells. 

I. L. Andrulis and M. T. Barrett. DNA methylation patterns associated with asparagine synthetase expression in asparagine-overproducing and auxotrophic cells. Mol. Cell. Biol. 9 2922 (1989). 

As I pointed out in chapter 3, one of the ways to regulate gene expression is to switch off genes by DNA methylation or switch them on by demethylation. DNA methylation patterns in ordinary (somatic) differentiated cells are usually stable, their methylation patterns are passed on to daughter cells when they divide. 

CondoreUi DF, Nicoletti VG, Barresi V, et al. (1994). Tissue-specific DNA methylation patterns of the rat gUal fibrillary acidic protein gene. J. Neurosci. Res., 39 694—707. 

A recent report has shown that DNA hypomethylation may contribute to the induction of tumors in mice via an epigenetic mechanism causing chromosomal instability. In addition to facilitating neoplastic transformation, alterations in DNA methylation patterns have been shown to exert effects on embryonic development and acquired drag resistance to cytotoxic agents. Recent data from oiu laboratory have demonstrated the... 

Aberrant gene expression due to DNA hypomethylation has also been observed in some breast cancers,in contrast to other findings that did not reveal any significant changes in DNA methylation patterns. " In another study, global DNA methylation analyses were performed in breast lesions and respective adjacent parenchyma DNA hypomethylation was significantly increased in breast carcinomas and proved to be a causative factor in tumor development. ... 

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