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

Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks mayhelp to clarify SCZ molecular basis.Wehave previously identified a dopamineD2receptor (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 enrichmentanalysis to identify transcription factor (TF) binding sites inhumanpromotersofgenescoexpressed withDRD2.Then,wemeasured 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,weanalyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) ofSCZpatients.Our in silico analysis revealedenrichmentforNURR1andERR1bindingsites.Inneuronalcultures, the expression ofgeneseither relevant toSCZrisk (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.