TY - JOUR T1 - <em>Zfp189</em> Mediates Stress Resilience Through a CREB-Regulated Transcriptional Network in Prefrontal Cortex JF - bioRxiv DO - 10.1101/403733 SP - 403733 AU - Zachary S. Lorsch AU - Peter J. Hamilton AU - Aarthi Ramakrishnan AU - Eric M. Parise AU - William J. Wright AU - Marine Salery AU - Ashley Lepack AU - Philipp Mews AU - Orna Issler AU - Andrew McKenzie AU - Xianxiao Zhou AU - Lyonna F. Parise AU - Stephen T Pirpinias AU - Idelisse Ortiz Torres AU - Sarah Montgomery AU - Yong-Hwee Eddie Loh AU - Benoit Labonté AU - Andrew Conkey AU - Ann E. Symonds AU - Rachael Neve AU - Gustavo Turecki AU - Ian Maze AU - Yan Dong AU - Bin Zhang AU - Li Shen AU - Rosemary C. Bagot AU - Eric J. Nestler Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/09/07/403733.abstract N2 - Stress 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. ER -