A zinc finger transcription factor enables social behaviors while 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 rodent prefrontal cortex was previously demonstrated 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. Following 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, inversion of ZFP189-mediated transcription in this brain area, achieved by viral 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. RNA sequencing of virally manipulated prefrontal cortex tissues reveals that ZFP189 transcription factors of opposing regulatory function (ZFP189WT versus ZFP189VPR) have opposite influence on the expression of genetic transposable elements as well as genes that participate in adaptive immune functions. Collectively, this work reveals that ZFP189 function in the prefrontal cortex coordinates structural and transcriptional neuroadaptations necessary for complex social behaviors while regulating transposable element-rich regions of DNA and the expression of 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.

Circadian and ultradian rhythms: Clinical implications

“…Functional pathway analysis (Fig. 2b [18]) revealed how a network of clock genes [23][24][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], GCinduced 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].…”