NURR1 and ERR1 Modulate the Expression of Genes of a DRD2 Coexpression Network Enriched for Schizophrenia Risk.

Autor:	Torretta S; Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari 70124, Italy., Rampino A; Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari 70124, Italy.; Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, 70124, Italy., Basso M; Laboratory of Transcriptional Neurobiology, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento 38123, Italy., Pergola G; Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari 70124, Italy.; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland 21205., Di Carlo P; Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari 70124, Italy.; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland 21205., Shin JH; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland 21205., Kleinman JE; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland 21205.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287., Hyde TM; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland 21205.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.; Departments of Neurology., Weinberger DR; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland 21205.; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.; Neuroscience.; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205., Masellis R; Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari 70124, Italy.; Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, 70124, Italy., Blasi G; Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari 70124, Italy.; Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, 70124, Italy., Pennuto M; Department of Biomedical Sciences, University of Padova, Padova 35131, Italy.; Veneto Institute of Molecular Medicine (VIMM), Padova 35129, Italy.; Dulbecco Telethon Institute, CIBIO, University of Trento, 38123, Italy.; Padova Neuroscience Center, 35131 Padova, Italy, and., Bertolino A; Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari 70124, Italy, alessandro.bertolino@uniba.it.; Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, 70124, Italy.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2020 Jan 22; Vol. 40 (4), pp. 932-941. Date of Electronic Publication: 2019 Dec 06.
DOI:	10.1523/JNEUROSCI.0786-19.2019
Abstrakt:	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 ( 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 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment. SIGNIFICANCE STATEMENT In 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 coexpressed 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 coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ. (Copyright © 2020 the authors.)
Databáze:	MEDLINE
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