CIUSSS Capitale nationale logo

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

Publication Type:

Journal Article

Source:

Nat Neurosci, Volume 22, Issue 9, p.1413-1423 (2019)

Keywords:

Adaptation, Psychological, Animals, Gene Regulatory Networks, Mice, Mice, Inbred C57BL, Prefrontal Cortex, Stress, Psychological, Transcription, Genetic, Zinc Fingers

Abstract:

<p>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.</p>

Funding / Support / Partners

logo FRQ-S logo ctrn logo fci logo cihr irsc logo nserc logo MESISentinelle nord