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

Abstract

Schizophrenia and bipolar disorder are complex mental disorders with risks contributed by multiple genes. Dysregulation of gene expression has been implicated, but little is known about such regulation systems in the human brain. We analyzed three transcriptome datasets using 394 brain tissue samples from patients with schizophrenia or bipolar disorder and healthy control individuals without known history of psychiatric disorders. We built genome wide co-expression networks that included microRNAs (miRNAs). We identified a co-expression network module that was differentially expressed between patients and 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 POU3F2, a gene also identified on a GWAS for bipolar disorder, could regulate hsa-miR-320e and other putative target mRNAs. These regulatory relationships were replicated by PsychENCODE/BrainGVEX data and validated by knockdown and overexpression experiments in the SH-SY5Y and neural progenitor cell lines in vitro. We identified a psychosis-associated brain gene expression module that was enriched for rare coding variants in genes associated with schizophrenia and contained the putative bipolar disorder risk gene POU3F2 as a key regulator of gene expression in this module.

Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder

“…Among the identified associations, convergent evidence suggested a critical etiologic role of POU3F2 in ASD. POU3F2 encodes a transcription factor mainly expressed in the central nervous system 19 and has known key regulatory roles in schizophrenia and bipolar disorder 22,23 . In our analysis, it reached transcriptome-wide statistical significance in trio-based TWAS and was successfully replicated in the case-control replication.…”

“…Among the 5 significant genes after a stringent Bonferroni correction for all genes and all tissues in the analysis (Figure 3 and Supplementary Figure 14), POU3F2 (also known as BRN2) encodes a neural transcription factor with important roles in neurogenesis and brain development 19 . It is a known risk gene for bipolar disorder 20,21 and has been identified as a master regulator of gene expression changes in schizophrenia and bipolar disorder 22,23 . Deletions resulting in loss of one copy of POU3F2 cause a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity 24 .…”

“…The transcription factor encoded by POU3F2 is a key regulator in multiple psychiatric disorders 22,23 . Based on its robust association with ASD in our analysis, we hypothesize that POU3F2 may also play a central role in ASD through its regulatory network.…”

Local genetic correlation analysis reveals heterogeneous etiologic sharing of complex traits

“…This is consistent with our recent finding that genes regulated by TF POU3F2 showed a 2.7-fold enrichment for loss-of-function de novo mutations in ASD probands which are known to cause comorbid intellectual disability 54 . These results hint at a pervasive, regulatory role of POU3F2 in cognitive ability and many neuropsychiatric disorders 55,56 . Regions showing opposite correlation directions between ASD and CP were enriched for distinct mechanistic pathways (Methods; Figure 5; Supplementary Tables 15-18).…”

From Sanger Sequencing to Genome Databases and Beyond

“…With special focus on schizophrenia, autism and bipolar disorder, the PsychENCODE study combined data from DNA and RNA sequencing methods toidentify the genome and the transcriptome withinformation regarding the DNA structure, transcription factors [5] and enhancer regions.…”