? Adverse childhood experiences are associated with increased risk of mental illness later in life, especially depression. Recent studies show that whether a person develops major depression following early stressful experiences is influenced by a polymorphism in the serotonin transporter gene (5-HTT: 5-hydroxytryptamine transporter). The molecular mechanisms by which early stress increases risk for depression in adulthood is not known, but is presumed to include epigenetic programming of gene expression. This team of researchers has developed an innovative gene-environment interaction screen (GxE screen) in mouse that allows for the first time a study examining the molecular mechanisms underlying epigenetic programming by early adverse environment through genetic manipulation of this animal model. Using the GxE screen the intent is to show that the effects of adverse rearing environment on anxiety-related behavior are modulated by mutations in 5-HTT in a way that mimics the interaction between early stress and 5-HTT seen in humans. These findings suggest that the molecular mechanisms involved in this model are relevant to the etiology of human depression. This proposal seeks to apply a novel high-throughput methvlation profiling technique to perform whole genome epigenetic profiling of mice from this screen. Experiments promise to identify genes that are epigenetically regulated by rearing environment and 5-HTT in mouse. These genes will become candidate susceptibility genes for major depression in humans and will serve as potential diagnostic and therapeutic targets in clinic. ? ? ? ?