We sought to identify hippocampal DMRs in the mouse associated with E2 exposure to model the molecular changes occurring during heightened estrogen levels in pregnancy. We chose to utilize hippocampal tissue because effects of E2 on mood are believed, in part, to be localized in the hippocampus, based on numerous studies including knockout experiments,22 17β-E2 administration experiments23 and selective estrogen receptor antagonists and agonists13,24,25 demonstrate anxiolytic and antidepressant effects of E2 exposure in rodents. Furthermore in rodent models, E2 administration has been shown to increase synaptic plasticity and dendritic spine density within the hippocampus,14,15 while withdrawal from pregnancy levels of E2 results in decreased hippocampal brain-derived neurotrophic factor (BDNF) expression16 and suppressed hippocampal neurogenesis.26 We identified 891 significant DMRs before correction for multiple testing. Of these, 380 DMRs exhibited a decrease and 511 exhibited an increase in DNA methylation in response to E2 (Figure 1 and Supplementary Table 3). Gene ontology (GO) analysis using GOstat27 identified a number of significantly enriched GO categories within genes proximal to the identified DMRs (Table 1). Motif enrichment analysis of genomic sequences of the
