One Gene with a Domino Effect on Social Behavior

Transcription factors that tune the expression of multiple genes could be key players in regulating behavior, but scientists need to scout for them. Peter Hamilton, a neuroscientist at Virginia Commonwealth University, has contributed to this search for years, especially in the context of social behavior studies. In 2019, he and his colleagues identified a transcription factor (TF) that correlated with stress resilience in rodents.1 In a recent study, Hamilton and his team discovered that the same TF orchestrates social behaviors in mice and unexpectedly links the brain and immune system.2 Their findings, reported in Translational Psychiatry, shed light on the genetics underpinning social conduct in mammals, laying the groundwork to identify genes contributing to mental illness.

The neural regulator that Hamilton identified in his original study belongs to the largest TF family in mammals, called the Krüppel-associated box (KRAB) zinc finger proteins (ZFP).3 Its members directly regulate genes and repress transposable elements—DNA sequences that regulate other genes.4,5 In the new study, Hamilton and his team explored how the TF in question, ZFP189, affects stress in mice by creating a synthetic version with flipped functionality; they swapped out its repressive domain for an activator one to disrupt its inhibitory effects on transposable elements. Then the researchers gave mice an extra copy of the Zfp189 gene, either the synthetic or the normal version. “There might be a sweet spot for transposable element regulation where too much or too little [ZFP189] could lead to dysregulation of social behaviors,” Hamilton explained.

Immediately, they could tell that the synthetic TF shook up neuron physiology. Neurons in the prefrontal cortex, a brain region pivotal to cognition that is sensitive to stress, grew more mushroom-shaped extensions in the mice that received the synthetic, activatory TF compared to the mice that received the repressive form.6 

Next, to find out how these disruptions impacted stress endurance in mice, the researchers placed mice with synthetic ZFP189 in a cage with a larger aggressive mouse.7 Usually, mice can endure minor hostility, but Hamilton noticed that these mice behaved differently: They withdrew socially. This tipped him off that in addition to affecting the stress response, ZFP189 might influence social behaviors more broadly. 

Curious as to how much ZFP189 influences group dynamics, his team conducted a social dominance tube test to explore whether mice with the synthetic TF could perceive social hierarchies.8 They placed two mice facing each other at the ends of a tube too narrow for either of them to turn around. Under normal circumstances, the dominant mouse would usually step forward while the subordinate mouse would retreat. “But when we put in our synthetic transcription factor, all bets were off, and the performance was just random chance,” Hamilton said. 

Half the time, the mice bearing the synthetic TF moved forward and half the time reversed, regardless of the social ladder, suggesting that they could not perceive it. “It indicates that this transcription factor facilitates the brain function that is required for social cognition,” Hamilton noted.

After realizing that this TF controls more cognitive faculties than expected, the team turned to RNA sequencing to find out what effect the synthetic TF had on the transcriptomes of neurons in the prefrontal cortex. The modified ZFP189 activated hundreds of transposable elements, which the researchers thought might trigger a domino effect on gene regulation. When they dug deeper, they discovered that the awakened transposable elements shut down an array of immune genes, whereas the normal version of ZFP189 switched on these immune factors. 

Discovering that ZFP189 normally activates immune genes puzzled the neuroscientists. The brain is an immune-privileged organ, meaning it has physical reinforcements that keep pathogens out and doesn’t require much immune surveillance as a result, so the team did not know what these immune factors do in the prefrontal cortex.9 Previously, scientists suggested that inflammation may lead individuals to withdraw from social situations to limit the spread of infection, so one hypothesis is that these immune genes might fuel reclusive behavior during sickness.10 

“It’s a trend in neuroscience to say the immune system and brain are closely linked,” said Didier Trono, a molecular geneticist researching KRAB ZFP at the Swiss Federal Institute of Technology in Lausanne who was not involved with the study. “Indeed, what seems to be a master regulator of some neuronal function also seems to be an important regulator of some immune function,” he added, suggesting that they might be physiologically coupled. Alternatively, Hamilton speculated that these immune factors could be repurposed for different unrelated functions in the brain.

ZFP189’s role in humans remains largely unchartered. “Even though this study was done in the mouse, it’s particularly interesting because it’s one of the KRAB ZFP for which there is a human ortholog,” Trono noted. 

Next, Hamilton plans to explore this TF’s role in neuropsychiatric disorders.  “It would be illuminating if this transposable element mechanism could explain some of the social deficits that are common to so many brain diseases,” he said.


1. Lorsch ZS, et al. Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortexNat Neurosci. 2019;22(9):1413-1423. 
2. Truby NL, et al. A zinc finger transcription factor enables social behaviors while controlling transposable elements and immune response in prefrontal cortexTransl Psychiatry. 2024;14(1):59. 
3. Playfoot CJ, et al. Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brainGenome Res. 2021;31(9):1531-1545. 
4. Yang P, et al. The role of KRAB-ZFPs in transposable element repression and mammalian evolutionTrends Genet. 2017;33(11):871-881.
5. Fueyo R, et al. Roles of transposable elements in the regulation of mammalian transcriptionNat Rev Mol Cell Biol. 2022;23(7):481-497.
6. Arnsten AFT. Stress signalling pathways that impair prefrontal cortex structure and functionNat Rev Neurosci. 2009;10(6):410-422. 
7. Lyons DM, et al. Ecological validity of social defeat stressors in mouse models of vulnerability and resilienceNeurosci Biobehav Rev. 2023;145:105032.
8. Fulenwider HD, et al. Manifestations of domination: Assessments of social dominance in rodentsGenes Brain Behav. 2022;21(3):e12731. 
9. Louveau A, et al. Revisiting the mechanisms of CNS immune privilegeTrends Immunol. 2015;36(10):569-577. 
10. Muscatell KA, Inagaki TK. Beyond social withdrawal: New perspectives on the effects of inflammation on social behavior. Brain Behav Immun. 2021;16:100302. 

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