title: Differential expression of transcriptional regulatory units in the prefrontal cortex of patients with bipolar disorder: potential role of early growth response gene 3.
abstract: Bipolar disorder (BD) is a severe mental illness with a strong genetic component. Despite its high degree of heritability, current genetic studies have failed to reveal individual loci of large effect size. In lieu of focusing on individual genes, we investigated regulatory units (regulons) in BD to identify candidate transcription factors (TFs) that regulate large groups of differentially expressed genes. Network-based approaches should elucidate the molecular pathways governing the pathophysiology of BD and reveal targets for potential therapeutic intervention. The data from a large-scale microarray study was used to reconstruct the transcriptional associations in the human prefrontal cortex, and results from two independent microarray data sets to obtain BD gene signatures. The regulatory network was derived by mapping the significant interactions between known TFs and all potential targets. Five regulons were identified in both transcriptional network models: early growth response 3 (EGR3), TSC22 domain family, member 4 (TSC22D4), interleukin enhancer-binding factor 2 (ILF2), Y-box binding protein 1 (YBX1) and MAP-kinase-activating death domain (MADD). With a high stringency threshold, the consensus across tests was achieved only for the EGR3 regulon. We identified EGR3 in the prefrontal cortex as a potential key target, robustly repressed in both BD signatures. Considering that EGR3 translates environmental stimuli into long-term changes in the brain, disruption in biological pathways involving EGR3 may induce an impaired response to stress and influence on risk for psychiatric disorders, particularly BD.
authors.affiliation: Bipolar Disorder Program, Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Laboratory of Cellular Biochemistry, Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: B
authors.initials: B
authors.lastname: Pfaffenseller
authors.affiliation: Bipolar Disorder Program, Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: P V
authors.initials: PV
authors.lastname: da Silva Magalhães
authors.affiliation: Laboratory of Cellular Biochemistry, Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: M A
authors.initials: MA
authors.lastname: De Bastiani
authors.affiliation: Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, Polytechnic Center, Curitiba, Brazil.
authors.forename: M A A
authors.initials: MA
authors.lastname: Castro
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Gallitano
authors.affiliation: Bipolar Disorder Program, Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: F
authors.initials: F
authors.lastname: Kapczinski
authors.affiliation: Laboratory of Cellular Biochemistry, Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: F
authors.initials: F
authors.lastname: Klamt
mesh_terms: D000293:Adolescent; D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics*; D051776:Early Growth Response Protein 3 / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D061346:Laser Capture Microdissection; D008297:Male; D008875:Middle Aged; D051903:Nuclear Factor 45 Protein / Q000235:genetics*; D017397:Prefrontal Cortex / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome; D051840:Y-Box-Binding Protein 1 / Q000235:genetics*; D055815:Young Adult
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; C079945:EGR3 protein, human; D020662:Guanine Nucleotide Exchange Factors; C494013:ILF2 protein, human; C105852:MADD protein, human; D051903:Nuclear Factor 45 Protein; C582288:TSC22D4 protein, human; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D051776:Early Growth Response Protein 3