Derepression of transposable elements in mouse prefrontal cortex disrupts social behavior

Area of Science:

• Neuroscience
• Synthetic Biology
• Genetics

Background:

• The Krüppel-associated box zinc finger protein (KZFP) interacting protein TRIM28 plays a role in gene regulation.
• TRIM28's function in the prefrontal cortex (PFC) and its impact on social behavior are not fully understood.

Purpose of the Study:

• To investigate the social behavioral consequences of altered TRIM28 function in the mouse PFC using a synthetic biology approach.
• To explore the regulatory mechanisms by which TRIM28 influences gene expression, transposable element (TE) stability, and social behavior.

Main Methods:

• Reprogramming of TRIM28 in mice by modifying its transcriptional regulatory domains to create TRIM28 ^VPR (activation) and TRIM28 ^NFD (no function) variants.
• Viral-mediated delivery of TRIM28 variants into the mouse PFC.
• In vitro validation using a KZFP-regulated luciferase reporter gene.
• RNA-sequencing to analyze transcriptional changes, including TE expression.
• Behavioral assays to assess social interaction and non-social behaviors.
• Reversal of social deficits by repletion of interferon cytokines.

Main Results:

• TRIM28 ^VPR activated reporter gene expression, while TRIM28 ^WT repressed it.
• Intra-PFC delivery of HSV-TRIM28 ^VPR reduced the salience of novel social interaction in both male and female mice without affecting non-social behaviors.
• HSV-TRIM28 ^VPR promoted the transcriptional escape of all classes of TEs, particularly those near downregulated immune genes.
• Social deficits induced by HSV-TRIM28 ^VPR were reversible upon intra-PFC repletion of interferon cytokines.

Conclusions:

• Prefrontal cortex KZFP-TRIM28 interactions are crucial for stabilizing TEs.
• TRIM28-mediated TE stabilization is necessary for the cis-regulation of key immune genes.
• Proper regulation of immune genes by TRIM28 is essential for complex, pro-social behaviors.