Previous research has demonstrated DNA methylation changes in

a number of genes following early life stress. Epigenetic mechanisms may play a key role in the translation of environmental factors into phenotype. The epigenome is particularly susceptible to external disruption during a number of key developmental periods, and is thought most vulnerable to the effect of environmental factors during early development (Dolinoy et al. 2007). In this way, it is possible that epigenetic adaptations in Inhibitors,research,lifescience,medical response to early life adversity may play an important role in developmental plasticity, mediating phenotypic variability later in life (Bateson et al. 2004). Our study found that a CpG site in an intergenic region near the Avp gene was hypermethylated in MS males in hippocampal tissue. A recent paper by Murgatroyd et al. (2009) found hypomethylation of multiple Inhibitors,research,lifescience,medical CpG sites in the same region, but only in tissue from the para-ventricular nucleus. These CpG sites, especially site 10, were associated with Avp expression differences, suggesting an important regulatory role for this region. We did not observe DNA methylation differences in any of the same sites as the Murgatroyd et al. (2009) study, although the discrepancies between the two studies may result from our use of a different brain tissue, and Enzastaurin because the CpG sites Inhibitors,research,lifescience,medical interrogated in our assay did not overlap completely with those of Murgatroyd et al. (2009). For example, CpG Unit 2 in our assay,

Inhibitors,research,lifescience,medical which corresponds to site 10 in the Murgatroyd study, was unable to be assessed and therefore we are unable to determine if there are DNA methylation differences between groups for that site. However, some sites were assessed in both studies and this provides interesting directions to explore in future research. CpG Unit 1 in our study, which shows a significant hypermethylation in maternally separated animals, is shown to decrease in DNA methylation over time (from 6 week mice to 1 year mice) in the Inhibitors,research,lifescience,medical Murgatroyd et al. (2009)

study, regardless of environment. This suggests that this site may be an area for variable DNA methylation, and in the case of the maternally separated animals a dysregulation of the decrease in DNA methylation over time could be a maladaptive response to early life stress. We find modest hypermethylation across a number of sites in the promoter region of the glucocorticoid receptor following MS, specifically in DBA/2J mice. More marked hypermethylation in this region of the glucocorticoid receptor promoter following a stressful event have been reported crotamiton by a number of groups (Weaver et al. 2004; Oberlander et al. 2008; Mcgowan et al. 2009), although these are not consistently found (Daniels et al. 2009). Weaver et al. (2004) observed that rat pups raised by mothers displaying reduced nursing behaviors (licking, grooming, and arched back nursing) demonstrate marked hypermethylation across a number of CpG sites, including a region containing an NGFI-a binding site (Weaver et al. 2004).