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Zfp189 Mediates Stress Resilience Through a CREB-Regulated Transcriptional Network in Prefrontal Cortex

ABSTRACT: Zfp189 Mediates Stress Resilience Through a CREB-Regulated Transcriptional Network in Prefrontal Cortex

PROVIDER: PRJNA485156 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7661110_1.fastq.gz	Fastqsanger.gz
	SRR7661110_2.fastq.gz	Fastqsanger.gz
	SRR7661120_1.fastq.gz	Fastqsanger.gz
	SRR7661120_2.fastq.gz	Fastqsanger.gz
	SRR7661130_1.fastq.gz	Fastqsanger.gz

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Zfp189 Mediates Stress Resilience Through a CREB-Regulated Transcriptional Network in Prefrontal Cortex

Project description:Stress resilience involves numerous brain-wide transcriptional changes. Determining the organization and orchestration of these transcriptional events may reveal novel antidepressant targets, but this remains unexplored. Here, we characterize the resilient transcriptome with co-expression analysis and identify a single transcriptionally-active uniquely-resilient gene network. Zfp189, a previously unstudied zinc finger protein, is the top network key driver and its overexpression in prefrontal cortical (PFC) neurons preferentially activates this network, alters neuronal activity and promotes behavioral resilience. CREB, which binds Zfp189, is the top upstream regulator of this network. To probe CREB-Zfp189 interactions as a network regulatory mechanism, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB selectively to the Zfp189 promoter. This single molecular interaction in PFC neurons recapitulates the pro-resilient Zfp189-dependent downstream effects on gene network activity, electrophysiology and behavior. These findings reveal an essential role for Zfp189 and a CREB-Zfp189 regulatory axis in mediating a central transcriptional network of resilience.

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Project description:To understand the mechanisms underlying resilience to chronic stress exposure observed in mice with disinhibited SST neurons (SSTCre:γ2f/f mice), we analyzed and compared the transcriptome profiles of the medial prefrontal cortex (mPFC) from male and female control (SSTCre) and mutant (SSTCre:γ2f/f) mice, with and without exposure to 21 days of chronic variable stress (CVS). We found that SSTCre:g2f/f male, but not female, mice are resilient to CVS-induced changes in the mPFC transcriptome. The CVS-induced transcriptome of stress-resilient male mice was characterized by fewer and distinct CVS-induced gene expression changes compared to the CVS-induced transcriptome of stress-vulnerable SSTCre controls. The transcriptome of non-stressed stress-resilient male mice showed stress-like transcriptome changes along with defects in signal transduction similar to stress exposed SSTCre stress-vulnerable controls. These features of non-stressed stress-resilient mice were normalized by chronic stress exposure, along with enhancement of mRNA translation. Stress-induced differentially expressed genes of stress-vulnerable, but not stress-resilient mice were prominently associated with risk genes of human stress-related psychiatric disorders.

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Project description:We report the application of high-throughput RNA sequencing to the human prefrontal cortex. The brain dataset was obtained by sequencing total RNAs extracted from the dorsolateral prefrontal cortex of five deceased human patients with no apparent pathology, followed by depletion of ribosomal RNA to obtain all non-rRNA coding and non-coding RNAs in the human brain transcriptome. Five samples were sequenced, four coming from frozen brain tissue (frontal cortex) of deceased female human patients with no remarkable pathology, and one from a male patient with no remarkable pathology.

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Transcription profiling of human prefrontal cortex during postnatal development

Project description:Fresh frozen post mortem prefrontal cortex tissue (Brodman area 46) was obtained from 44 individuals varying in age from 0 to 49 years. RNA was extracted from these samples and hybridized to HG133plus2.0 GeneChips. The data was used to examine patterns of gene expression over the course of human postnatal developmental and ageing. PMI - postmortem interval, DLPFC - dorsolateral prefrontal cortex Experiment Overall Design: The dataset consists of 44 individuals varying in age from 0 to 49 years

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