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NURR1 and ERR1 modulate the expression of genes of a DRD2 co-expression network enriched for schizophrenia risk.

Authors
  • Torretta, Silvia1
  • Rampino, Antonio1, 2
  • Basso, Manuela3
  • Pergola, Giulio1, 4
  • Di Carlo, Pasquale1, 4
  • Shin, Joo H4
  • Kleinman, Joel E4, 5
  • Hyde, Thomas M4, 5, 6
  • Weinberger, Daniel R4, 5, 7, 8
  • Masellis, Rita1, 2
  • Blasi, Giuseppe1, 2
  • Pennuto, Maria9, 10, 11, 12
  • Bertolino, Alessandro13, 2
  • 1 Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, 70124, Italy. , (Italy)
  • 2 Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, 70124, Italy. , (Italy)
  • 3 Laboratory of Transcriptional Neurobiology, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, 38123, Italy. , (Italy)
  • 4 Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, 21205, USA.
  • 5 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA.
  • 6 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • 7 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
  • 8 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
  • 9 Department of Biomedical Sciences (DBS), University of Padova, 35131, Italy. , (Italy)
  • 10 Veneto Institute of Molecular Medicine (VIMM), Padova, 35129, Italy. , (Italy)
  • 11 Dulbecco Telethon Institute, CIBIO, University of Trento, 38123, Italy. , (Italy)
  • 12 Padova Neuroscience Center (PNC), 35131 Padova, Italy. , (Italy)
  • 13 Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, 70124, Italy [email protected] , (Italy)
Type
Published Article
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Publication Date
Dec 06, 2019
Identifiers
DOI: 10.1523/JNEUROSCI.0786-19.2019
PMID: 31811028
Source
Medline
Language
English
License
Unknown

Abstract

Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of co-expressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) co-expression 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 co-expression module and their relevance to SCZ.We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes co-expressed 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 co-expression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. 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 co-expression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENTIn the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes co-expressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that co-expression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ. Copyright © 2019 the authors.

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