부산대학교 도서관

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 Zfp189in 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 Zfp189promoter. To probe CREB–Zfp189interactions, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB or G9a (a repressive histone methyltransferase) to the Zfp189promoter in prefrontal cortex neurons. Induction of Zfp189with site-specific CREB is pro-resilient, whereas suppressing Zfp189expression with G9a increases susceptibility. These findings reveal an essential role for Zfp189and CREB–Zfp189interactions in mediating a central transcriptional network of resilience. Researchers identify a transcriptional network engaged in stress-resilient mice that is regulated by a previously unstudied transcription factor, Zfp189, and elucidate molecular mechanisms controlling this network and resilience behavior.