Derepression of transposable elements in the mouse prefrontal cortex disrupts social behavior

• 成果类型: Article
• 署名作者: Kim, R. Kijoon; Smith, Corinne; Truby, Natalie L.; Strandberg, Shelbey R.; Bell, Jessica L.; Carwile, Nic; Silva, Gabriella M.; Neve, Rachael L.; Aung, Theingi; Cui, Xiaohong; Hamilton, Peter J.
• 署名单位: Virginia Commonwealth University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2510663122
• 发表日期: 2025-12-23
• 页码: e2510663122
• 关键词: transposable elements; TRIM28; Social behavior; prefrontal cortex; HIPPOCAMPAL-LESIONS; Object recognition; sex-differences; expression; EVOLUTION; dissociation; coevolution; IMPACT; memory; MAZE

摘要

The neurobiological origins of social behaviors are poorly understood. Previous studies have linked the function of a single Kr & uuml;ppel-associated box zinc finger protein (KZFP), ZFP189, in the mouse prefrontal cortex (PFC), with the regulation of transposable elements (TEs), immune genes, and social behaviors. Here, we expand the scope of inquiry to explore the relationship between collective PFC KZFP function and social behaviors by altering the function of the cognate KZFP interacting protein TRIM28 within the PFC of male and female mice. We reprogrammed natural TRIM28WT by replacing the endogenous, transcriptionally repressive domain with a synthetic, enhanced transcriptional activation domain VP64-p65-Rta (TRIM28VPR) or by excising the transcriptional regulatory domain (TRIM28NFD). Upon intra-PFC viral-mediated delivery of TRIM28 variants, we observed that inversion of TRIM28 transcriptional control via HSV-TRIM28VPR selectively produced deficits in social behaviors, without affecting nonsocial behaviors. RNA sequencing of manipulated PFC revealed that HSV-TRIM28VPR drove transcriptional escape of all classes of TEs, particularly those located within intronic and enhancer regions proximal to downregulated immune genes. HSV-TRIM28VPR-mediated social deficits were reversible by intra-PFC repletion of interferon cytokines. These data point to PFC KZFP-TRIM28 interactions as necessary to stabilize genomic TEs to enable cis-regulation of key immune gene expression, which enhances organismal capacity for complex, prosocial behaviors.