Derepression of transposable elements in mouse prefrontal cortex disrupts social behavior

Abstract Here, we present a synthetic biology approach to assess the social behavioral consequences of altered function of the Krüppel-associated box zinc finger protein (KZFP) interacting protein TRIM28 within the prefrontal cortex (PFC) of male and female mice. We reprogrammed natural TRIM28 WT by replacing the transcriptionally repressive domain with an enhanced transcriptional activation domain VP64-p65-Rta (TRIM28 VPR ), or by excising the transcriptional regulatory domain (TRIM28 NFD ). In vitro validation confirmed that TRIM28 WT represses, and TRIM28 VPR activates, the expression of a KZFP-regulated luciferase reporter gene. Upon intra-PFC viral-mediated delivery of TRIM28 variants, we observed that inversion of TRIM28 transcriptional control via HSV-TRIM28 VPR reduced the salience of novel social interaction for male and female mice while not affecting non-social behaviors. RNA-sequencing revealed HSV-TRIM28 VPR promoted transcriptional escape of all classes of TEs, particularly those located within intronic and distal enhancer regions of downregulated immune genes. HSV-TRIM28 VPR -driven social deficits were reversible by intra-PFC repletion of interferon cytokines. These novel data point to PFC KZFP-TRIM28 interactions as necessary to stabilize TEs to enable cis-regulation of key immune gene expression and enhance organismal capacity for complex, pro-social behaviors.