DOI
https://doi.org/10.25772/NWEP-PH84
Author ORCID Identifier
https://orcid.org/0000-0001-6891-6654
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Anatomy & Neurobiology
First Advisor
Peter Hamilton
Abstract
Neuropsychiatric disorders, such as major depressive disorder (MDD), represent a significant public health burden, with social withdrawal emerging as a core symptom across many of these conditions. Understanding the brain molecular mechanisms underlying social behavior is therefore critical for developing targeted therapeutic interventions to improve social functioning in affected individuals. This dissertation investigates the role of ZFP189, a KRAB zinc finger protein (KZFP), in governing social behavior by controlling immune gene expression and transposable element (TE) regulation in the prefrontal cortex (PFC). TEs, also known as “jumping genes,” are repetitive DNA sequences capable of mobilization and genomic re-integration, and are also capable of influencing gene expression and regulatory networks. Using synthetic biology approaches, we demonstrate that ZFP189-mediated transcriptional control in PFC is essential for the maintenance of social behaviors, with dysregulation leading to deficits in social interaction, motivation, and awareness of social hierarchy. RNA sequencing of virally manipulated PFC tissues reveals that ZFP189 transcription factors (TFs) with opposing regulatory functions exert opposing effects on the expression of TEs and immune-related genes. This work demonstrates that ZFP189 in the PFC governs structural and molecular adaptations essential for social behavior, with its regulation of TE-driven immune gene expression potentially reflecting an evolutionary mechanism to support social group functioning. We further validate this social-immune interaction by showing that co-delivery of ZFP189VPR and TNFα to the PFC partially rescues social deficits. Additionally, we show that ZFP189 over expression (ZFP189WT) promotes stress resilience, whereas reversing ZFP189-mediated transcription (ZFP189VPR) enhances stress vulnerability. Extending our investigation to human neuropsychiatric disorders, we identify a robust downregulation of TE transcripts in the cortical brain regions of individuals with MDD, suggesting that TE dysregulation may be a previously underappreciated molecular signature of MDD. Collectively, this work positions ZFP189 as a key molecular regulator of social behavior and stress resilience, with broader implications for neuropsychiatric disorders. Future research should explore the therapeutic potential of targeting ZFP189-TE interactions to modulate social and stress-related behaviors in neuropsychiatric conditions.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-20-2025