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Sci Transl Med. 2018 Dec 19;10(472). pii: eaat8178. doi: 10.1126/scitranslmed.aat8178. Epub 2018 Dec 13.

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

Author information

1
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China. chenchao@sklmg.edu.cn liuch@upstate.edu.
2
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
3
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
4
Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.
5
Child Health Institute of New Jersey, Department of Neuroscience, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
6
Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
7
Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
8
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
9
Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, NY, USA.
10
Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
11
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
12
School of Public Health, University of Illinois at Chicago, Chicago, IL, USA.
13
Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
14
The Second Xiangya Hospital, Central South University, Changsha, China.
15
Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
16
LifeSpan Changes in Brain and Cognition (LCBC), Department of Psychology, University of Oslo, Oslo, Norway.
17
Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA.
18
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
19
Tempus Labs Inc., Chicago, IL, USA.
20
Department of Psychology, Shaanxi Normal University, Xi'an, China.

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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