Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex

Abstract

Understanding transcriptional changes engaged in stress resilience may reveal novel antidepressant targets. Here, we use gene co-expression analysis of RNA-sequencing data from brains of resilient mice to identify a gene network that is unique to resilience. Zfp189, which encodes a previously unstudied zinc finger protein, is the highest-ranked key driver gene in the network, and overexpression of Zfp189 in prefrontal cortical (PFC) neurons preferentially activates this network and promotes behavioral resilience. The transcription factor CREB is a predicted upstream regulator of this network and binds to the Zfp189 promoter. To probe CREB- Zfp189 interactions, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB or G9a (a repressive histone methyltransferase) to the Zfp189 promoter in PFC neurons. Induction of Zfp189 with site-specific CREB is pro-resilient, whereas suppressing Zfp189 expression with G9a increases susceptibility. These findings reveal an essential role for Zfp189 and CREB- Zfp189 interactions in mediating a central transcriptional network of resilience.

Modeling gene x environment interactions in PTSD using glucocorticoid-induced transcriptomics in human neurons

“…Relative to vehicle (0nM HCort), a total of 221, 2,945, and 2,441 genes were significantly differentially expressed ( q -value< 0.05) in NGN2 -neurons following incubation with 100 nM, 1000 nM, and 2500 nM of HCort, respectively ( Figure 1D, Supplemental Table 1 ). Notably, no single gene was significantly differentially expressed in response to HCort in mixed FB neurons, consistent with a previous report of minimal glucocorticoid response in mixed FB neurons 13 . Transcriptome-wide concordance was examined using HCort-associated log2 fold-changes and divergent patterns of differential responses were observed between mixed FB and NGN2 -neurons ( Figure 1E ).…”

“…Notably, glucocorticoid receptor signaling in blood and brain are convergent in murine models and highly associated with individual differences in response to trauma exposure 10 . Nevertheless, the degree to which PTSD symptoms arise as a result of elevated/sustained peripheral response to stress 8,10 and/or abnormal neuronal or circuit response to peripheral stress cues 11–13 remains unresolved. This work seeks to uncover GxE interactions between heritable genetic and/or epigenetic factors with stress exposure utilizing PTSD patient-derived human neurons.…”

Stress-induced epigenetic regulation of transcription in neocortical excitatory neurons drives depression-like behavior

“…This dimorphic effect on Crhr1 may be due to a sex-specific function of the CRH system in the PFC. Previous work demonstrates the presence of higher basal CRH levels in female PFCs than in males as well as sex-specific behavioral outcomes to CRH activation of neural circuits in the PFC 75 . We also observed significantly higher levels of Crhr1 in the medial PFC of female mice compared to age-matched male littermates (Supplemental Fig 7b).…”

RiboTag-Seq Reveals the Activation of the Unfolded Protein Response in Striatal Microglia Induced by Ethanol Withdrawal

“…The full list of genes in this module reflect a range of genes that encode both well-known and novel proteins (Figure 6a) and the most central genes of this module reflect the coregulation of the entire module. These most central genes have been framed as “hub” genes in other studies 41 although they may or may not directly regulate the other genes with which they are correlated. In order to further interpret this gene module, we performed over-representation analysis on this gene set, which is analogous to GSEA and we found that, among these were gene sets relating to the unfolded protein response (UPR).…”