These trans-acting factors recruit HATs to the target gene resulting in increased histone acetylation, chromatin opening, and increased accessibility of the DNA to demethylases. Since methylation of cytosine is an extremely stable chemical bond on DNA, this modification will

remain stable for years. For methylation signals to serve as stable markers, they should Inhibitors,research,lifescience,medical not be responsive to transient chromatin noise or short-term signals. The mechanism proposed here also allows for a reversal of the methylation marker by a similar intense change in chromatin structure later in life.99,110 This model has important implications on our understanding of how environmental signals, such as variations in maternal care, might stably alter glucocorticoid gene expression. DNA methylation marks genes for silencing by a number of mechanisms. The first mechanism is indirect and links DNA methylation to inactive chromatin structure. A region of methylated DNA juxtaposed

to regulatory regions of genes attracts different members of a family of methylated DNA Inhibitors,research,lifescience,medical binding proteins, such as methylCpG-binding protein, MeCP2, which recruits HDACs105,106 and histone methyltransferases111 to methylated genes.91,112 This results in a modification of chromatin around the gene precipitating an inactive chromatin structure. A different mechanism, which is relevant to our discussion Inhibitors,research,lifescience,medical here, involves direct interference of a specific methylated CpG residing within a response element for a transcription factor with the interaction of a transcription Inhibitors,research,lifescience,medical factor, such as the inhibition of binding of cMyc to its response element when it is methylated.113 Essentially,

the methylated cytosine serves as a mutation of the recognition element, functionally reducing the binding affinity of the response element for its transcription factor. A third mechanism involves a combination of binding of a methylated DNA binding protein and inhibition of activity of a transcription factor.114 While the first mechanism is dependent on the general density of methyl cytosines within the region associated with a gene rather than Inhibitors,research,lifescience,medical methylation of a specific CpG, the second mechanism requires a discrete methylation event and is relevant to the PD184352 (CI-1040) mechanism proposed here. The important consideration is the stability of cytosine methylation, which is preserved by covalent carbon-carbon bonds and could therefore serve as a long-term genomic “memory” of early experience influencing chromatin structure and GR expression in offspring of highand low-LG mothers. GR gene expression is increased throughout the hippocampus in the adult offspring of high-LG compared with low-LG mothers.39 The exon 17 GR promoter sequence appears to be significantly more active in the adult offspring of high-LG compared with low-LG mothers and was therefore the focus of ZD1839 purchase initial studies of possible maternal effects on DNA methylation.