Research ArticlePSYCHIATRIC DISEASE

The transcription factor POU3F2 regulates a gene coexpression network in brain tissue from patients with psychiatric disorders

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Science Translational Medicine  19 Dec 2018:
Vol. 10, Issue 472, eaat8178
DOI: 10.1126/scitranslmed.aat8178

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Illuminating the genomic mysteries of psychiatric diseases

Schizophrenia and bipolar disorder are complex psychiatric diseases with risks contributed by multiple genes. Studies by the PsychENCODE Consortium, including two in this issue (Chen et al. and Meng et al.), seek to elucidate the genomic elements and regulatory pathways that underpin several psychiatric disorders. Chen et al. analyzed transcriptome data from postmortem brain tissue from patients with schizophrenia or bipolar disorder. They report that the transcription factor POU3F2 is a core regulator of a gene coexpression network associated with these disorders. In a genome-wide analysis of control human brain samples from the adult and developing brain, Meng et al. report that the lncRNA DGCR5, which lies within the 22q11.2 deletion associated with schizophrenia risk, regulates expression of several SCZ-associated protein-coding genes.

Abstract

Schizophrenia and bipolar disorder are complex psychiatric diseases with risks contributed by multiple genes. Dysregulation of gene expression has been implicated in these disorders, but little is known about such dysregulation in the human brain. We analyzed three transcriptome datasets from 394 postmortem brain tissue samples from patients with schizophrenia or bipolar disorder or from healthy control individuals without a known history of psychiatric disease. We built genome-wide coexpression networks that included microRNAs (miRNAs). We identified a coexpression network module that was differentially expressed in the brain tissue from patients compared to healthy control individuals. This module contained genes that were principally involved in glial and neural cell genesis and glial cell differentiation, and included schizophrenia risk genes carrying rare variants. This module included five miRNAs and 545 mRNAs, with six transcription factors serving as hub genes in this module. We found that the most connected transcription factor gene POU3F2, also identified on a genome-wide association study for bipolar disorder, could regulate the miRNA hsa-miR-320e and other putative target mRNAs. These regulatory relationships were replicated using PsychENCODE/BrainGVEX datasets and validated by knockdown and overexpression experiments in SH-SY5Y cells and human neural progenitor cells in vitro. Thus, we identified a brain gene expression module that was enriched for rare coding variants in genes associated with schizophrenia and that contained the putative bipolar disorder risk gene POU3F2. The transcription factor POU3F2 may be a key regulator of gene expression in this disease-associated gene coexpression module.

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