biostudies-literatureLorsch ZSHope for Depression Research FoundationMQ Mental Health ResearchNIDA NIH HHSNIMH NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on Drug AbuseU.S. Department of Health & Human Services | NIH | National Institute of Mental Health1413-1423https://www.ebi.ac.uk/biostudies/studies/S-EPMC6713580biostudies-literatureUnknown22(9)Understanding the transcriptional changes that are 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 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 prefrontal cortex 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.Nature neuroscienceStress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.PMC6713580P50 MH096890R01 MH116900R01 MH051399P50MH096890MQ15FIP100011P01 DA047233R01MH051399R37 DA007359K99DA045795T32MH096678R00 DA045795K99 DA045795R01 DA007359F30MH110073McKenzie AShen LParise EMDong YMontgomery SEWright WJOrtiz Torres ISymonds AESalery MConkey ALepack AELoh YEZhang BMews PLorsch ZSRamakrishnan AParise LFLabonte BZhou XNestler EJPirpinias STTurecki GHamilton PJNeve RLBagot RCKronman HGMaze IIssler OfalseStress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.Understanding the transcriptional changes that are 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 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 prefrontal cortex 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.2019-01-01T00:00:00Z2019 Sep2024-12-03T15:33:34.915Z2020-05-22T10:32:24ZS-EPMC67135803142777010.1038/s41593-019-0462-8