Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.
Zachary S LorschPeter J HamiltonAarthi RamakrishnanEric M PariseMarine SaleryWilliam J WrightAshley E LepackPhilipp MewsOrna IsslerAndrew McKenzieXianxiao ZhouLyonna F PariseStephen T PirpiniasIdelisse Ortiz TorresHope G KronmanSarah E MontgomeryYong-Hwee Eddie LohBenoit LabontéAndrew ConkeyAnn E SymondsRachael L NeveGustavo TureckiIan MazeYan DongBin ZhangLi ShenRosemary C BagotEric J NestlerPublished in: Nature neuroscience (2019)
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.
Keyphrases
- transcription factor
- prefrontal cortex
- genome wide
- gene expression
- climate change
- dna methylation
- genome wide identification
- social support
- poor prognosis
- single cell
- copy number
- spinal cord
- dna binding
- depressive symptoms
- cell proliferation
- major depressive disorder
- big data
- bipolar disorder
- machine learning
- insulin resistance
- network analysis
- heat stress
- skeletal muscle
- genome editing
- high fat diet induced