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

Nat Neurosci. 2019 Sep;22(9):1413-1423. doi: 10.1038/s41593-019-0462-8. Epub 2019 Aug 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Psychological / physiology*
  • Animals
  • Gene Regulatory Networks / genetics
  • Mice
  • Mice, Inbred C57BL
  • Prefrontal Cortex / metabolism
  • Stress, Psychological / genetics*
  • Transcription, Genetic
  • Zinc Fingers / genetics*