期刊
NATURE NEUROSCIENCE
卷 22, 期 9, 页码 1413-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41593-019-0462-8
关键词
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资金
- National Institutes of Health [F30MH110073, T32GM007280, T32MH096678, K99DA045795, U01AG046170, R01AG057907, RF1AG057440, P50MH096890, R01MH051399]
- Hope for Depression Research Foundation
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.
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