Author:
Lorsch Zachary S.,Hamilton Peter J.,Ramakrishnan Aarthi,Parise Eric M.,Wright William J.,Salery Marine,Lepack Ashley,Mews Philipp,Issler Orna,McKenzie Andrew,Zhou Xianxiao,Parise Lyonna F.,Pirpinias Stephen T,Torres Idelisse Ortiz,Montgomery Sarah,Loh Yong-Hwee Eddie,Labonté Benoit,Conkey Andrew,Symonds Ann E.,Neve Rachael,Turecki Gustavo,Maze Ian,Dong Yan,Zhang Bin,Shen Li,Bagot Rosemary C.,Nestler Eric J.
Abstract
SummaryStress resilience involves numerous brain-wide transcriptional changes. Determining the organization and orchestration of these transcriptional events may reveal novel antidepressant targets, but this remains unexplored. Here, we characterize the resilient transcriptome with co-expression analysis and identify a single transcriptionally-active uniquely-resilient gene network. Zfp189, a previously unstudied zinc finger protein, is the top network key driver and its overexpression in prefrontal cortical (PFC) neurons preferentially activates this network, alters neuronal activity and promotes behavioral resilience. CREB, which binds Zfp189, is the top upstream regulator of this network. To probe CREB-Zfp189 interactions as a network regulatory mechanism, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB selectively to the Zfp189 promoter. This single molecular interaction in PFC neurons recapitulates the pro-resilient Zfp189-dependent downstream effects on gene network activity, electrophysiology and behavior. These findings reveal an essential role for Zfp189 and a CREB-Zfp189 regulatory axis in mediating a central transcriptional network of resilience.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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