A zinc finger transcription factor tunes social behaviors by controlling transposable elements and immune response in prefrontal cortex

Abstract

The neurobiological origins of social behaviors are incompletely understood. Here we utilized synthetic biology approaches to reprogram the function of ZFP189, a transcription factor whose expression and function in the rodent prefrontal cortex was previously determined to be protective against stress-induced social deficits. We created novel synthetic ZFP189 transcription factors including ZFP189VPR, which activates the transcription of target genes and therefore exerts opposite functional control from the endogenous, transcriptionally repressive ZFP189WT. Upon viral delivery of these synthetic ZFP189 transcription factors to mouse prefrontal cortex, we observe that ZFP189-mediated transcriptional control promotes mature dendritic spine morphology on transduced pyramidal neurons. Interestingly, dysregulation of ZFP189-mediated transcription in this brain area, achieved by delivery of synthetic ZFP189VPR, precipitates social behavioral deficits in terms of social interaction, motivation, and the cognition necessary for the maintenance of social hierarchy, without other observable behavioral deficits. By performing RNA sequencing in virally manipulated prefrontal cortex tissues, we discover that ZFP189 transcription factors of opposing regulatory function have opposite influence on the expression of genetic transposable elements as well as genes that participate in immune functions. Collectively, this work reveals that ZFP189 function in the prefrontal cortex coordinates structural and transcriptional neuroadaptations necessary for social behaviors by binding transposable element-rich regions of DNA to regulate immune-related genes. Given the evidence for a co-evolution of social behavior and the brain immune response, we posit that ZFP189 may have evolved to augment brain transposon-associated immune function as a way of enhancing an animal's capacity for functioning in social groups.

Histone H1x in mouse ventral hippocampus correlates with, but does not cause behavioral adaptations to stress

“…Although our viral vector did successfully increase intra-vHipp levels of H1x protein, we did not find any behavioral consequences of vHipp H1x OE, regardless of an animal's level of stress exposure or its determined stress-related phenotype. We feel this is important to report, since there is a robust body of literature that has identified brain molecular profiles that diverge across stress-resilient and stress-susceptible mice, and have often described perturbations of these brain processes as causally controlling the emergence of stress-related behaviors [7][8][9][10][26][27][28][29][30] , including in the vHipp [31][32][33][34][35][36][37] . Despite these past insights into the brain molecular mechanisms that control stress response, it is reasonable that not all molecular profiles correlated with stress response are singularly sufficient to drive the emergence of stress-related behaviors.…”

Neurobiology of Pathogen Avoidance and Mate Choice: Current and Future Directions

“…Indeed, recent work has suggested a co-evolution of social behaviour and immune responses. A zinc finger transcription factor, ZFP189, was shown to modulate social behaviour by controlling transposable elements and immune responses in the prefrontal cortex of mice [139]. This was based on earlier work suggesting a co-evolutionary link between social behaviour and anti-pathogen immune responses driven by interferon-γ signalling [140].…”

Circadian and ultradian rhythms: Clinical implications

“…Functional pathway analysis (Fig. 2b [18]) revealed how a network of clock genes [23–25] – including Per1, Per3, circadian associated repressor of transcription, basic helix‐loop–helix protein 40 and aralkylamine N ‐acetyltransferase – were linked to a large number of synaptic‐regulating genes – Calcium calmodulin‐dependent protein kinases (Camk2a, Camk2d) [26], small GTPase Rab8b [27, 28], intracellular calcium‐binding protein (Calb2) [29], cholecystokinin [30, 31], metabotropic glutamate receptor 2 [32], N ‐methyl‐ d ‐aspartate (NMDA) receptor subunit 2a (Grin2a) [33], Double C2 Domain Beta [34, 35] and membrane‐associated guanylate kinase scaffold proteins [36] (Mpp3, Mpp4) – via a hub of GC‐regulated genes, including Per1[17], Kruppel like factor 9 [37, 38], GC‐induced leucine zipper TSC Domain family member (Tsc22d3) [39] and Calcium calmodulin‐dependent protein kinase 2A (Camk2a) [40], with additional functional inputs from the transcription factor Zinc finger protein 189 [41]. Tetratricopeptide Repeat, Ankyrin Repeat And Coiled‐Coil Containing 1 gene that encodes a post‐synaptic density‐associated scaffolding protein [42] was also an intrinsic link in the network [18].…”