Journal
JOURNAL OF NEUROSCIENCE
Volume 40, Issue 4, Pages 932-941Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0786-19.2019
Keywords
coexpression; DLPFC; DRD2; NURR1 and ERR1; schizophrenia; treatment with antipsychotics
Categories
Funding
- Italian Ministry of Health [PE-2011-02347951]
- Lieber Institute for Brain Development
- Hoffmann-La Roche Collaboration Grant
- Association Francaise contre les Myopathies [22221]
- Telethon-Italy and Provincia Autonoma di Trento [TCP12013]
- European Union Seventh Framework Programme for research, technological development, and demonstration [602450]
- European Union's Horizon2020 research and innovation program under the Marie Sklodowska-Curie Grant [798181]
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Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1,Cnr1) or indexing coexpression in our module (Rtg4,Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nuni and Eng . Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.
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