Early Life Stress Alters Transcriptional Patterns and Gene Network Structures by Epigenetic Regulation

Abstract

Early life stress (ELS) increases the risk for depression and other psychiatric disorders in adulthood by heightening sensitivity to future stressors, as proposed by the “two-hit” stress hypothesis. However, the neurobiological mechanisms of this relationship are still unclear. Previous work using mouse models suggests that ELS primes for future stress susceptibility by inducing long-lasting transcriptional changes in the ventral tegmental area (VTA), a central reward-processing region of the brain. This priming effect is suspected to occur by increased levels of histone 3 lysine 4 mono-methylation (H3K4me1) and its specific mono-methyltransferase Setd7, which maintain regions of open chromatin for increased gene transcription. To understand how ELS primes for future stress susceptibility, we overexpressed Setd7 in mice VTA during the sensitive late postnatal period as a molecular substitute for ELS and examined changes in the epitranscriptome after exposure to chronic social defeat stress in adulthood. Through differential gene expression analysis, we found that Setd7 overexpression and/or exposure to adult stress induces significant changes to gene transcription patterns, characterized by the stimulus-specific upregulation and more generalized downregulation of genes relative to control mice. Furthermore, using weighted gene coexpression network analysis (WGCNA), I generated whole-genome networks for the GFP and Setd7 cohorts and identified key modules and hub genes associated with adult stress. Comparing the GFP and Setd7 networks by module preservation analysis revealed that Setd7 overexpression alters the structures of different gene networks in heterogeneous ways, speaking to the complexity of ELS and its impact on the epitranscriptome. In sum, the present thesis project has identified epigenetic regulation of transcription and changes to gene networks as potential mechanisms of the ELS “priming” effect. Future directions might experimentally modulate biologically significant hub genes and modules found in this study to test for regulatory effects and potential therapeutic applications.