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

Zachary S. Lorsch, Peter J. Hamilton, Aarthi Ramakrishnan, Eric M. Parise, Marine Salery, William J. Wright, Ashley E. Lepack, Philipp Mews, Orna Issler, Andrew McKenzie, Xianxiao Zhou, Lyonna F. Parise, Stephen T. Pirpinias, Idelisse Ortiz Torres, Hope G. Kronman, Sarah E. Montgomery, Yong Hwee Eddie Loh, Benoit Labonté, Andrew Conkey, Ann E. SymondsRachael L. Neve, Gustavo Turecki, Ian Maze, Yan Dong, Bin Zhang, Li Shen, Rosemary C. Bagot, Eric J. Nestler

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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.

Original languageEnglish
Pages (from-to)1413-1423
Number of pages11
JournalNature Neuroscience
Issue number9
StatePublished - 1 Sep 2019


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