title: Transcriptomic Analysis Shows Decreased Cortical Expression of NR4A1, NR4A2 and RXRB in Schizophrenia and Provides Evidence for Nuclear Receptor Dysregulation.
abstract: Many genes are differentially expressed in the cortex of people with schizophrenia, implicating factors that control transcription more generally. Hormone nuclear receptors dimerize to coordinate context-dependent changes in gene expression. We hypothesized that members of two families of nuclear receptors (NR4As), and retinoid receptors (RARs and RXRs), are altered in the dorsal lateral prefrontal cortex (DLPFC) of people with schizophrenia. We used next generation sequencing and then qPCR analysis to test for changes in mRNA levels for transcripts encoding nuclear receptors: orphan nuclear receptors (3 in the NR4A, 3 in the RAR, 3 in the RXR families and KLF4) in total RNA extracted from the DLPFC from people with schizophrenia compared to controls (n = 74). We also correlated mRNA levels with demographic factors and with estimates of antipsychotic drug exposure (schizophrenia group only). We tested for correlations between levels of transcription factor family members and levels of genes putatively regulated by these transcription factors. We found significantly down regulated expression of NR4A1 (Nurr 77) and KLF4 mRNAs in people with schizophrenia compared to controls, by both NGS and qPCR (p = or <0.01). We also detected decreases in NR4A2 (Nurr1) and RXRB mRNAs by using qPCR in the larger cohort (p<0.05 and p<0.01, respectively). We detected decreased expression of RARG and NR4A2 mRNAs in females with schizophrenia (p<0.05). The mRNA levels of NR4A1, NR4A2 and NR4A3 were all negative correlated with lifetime estimates of antipsychotic exposure. These novel findings, which may be influenced by antipsychotic drug exposure, implicate the orphan and retinoid nuclear receptors in the cortical pathology found in schizophrenia. Genes down stream of these receptors can be dysregulated as well, but the direction of change is not immediately predictable based on the putative transcription factor changes.
authors.affiliation: Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Corley
authors.affiliation: Schizophrenia Research Institute, Randwick, NSW, Australia.|Neuroscience Research Australia, Randwick, NSW, Australia.|School of Psychiatry, University of New South Wales Sydney, NSW, Australia.
authors.forename: Shan-Yuan
authors.identifier: http://orcid.org/0000-0002-0877-9114
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Wilkins
authors.affiliation: Schizophrenia Research Institute, Randwick, NSW, Australia.|Neuroscience Research Australia, Randwick, NSW, Australia.|School of Psychiatry, University of New South Wales Sydney, NSW, Australia.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Shannon Weickert
mesh_terms: D000328:Adult; D000368:Aged; D001344:Autopsy; D000075202:Contraindications; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008297:Male; D008875:Middle Aged; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000235:genetics*; D017397:Prefrontal Cortex / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D049230:Retinoid X Receptor beta / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D017423:Sequence Analysis, RNA / Q000379:methods; D055815:Young Adult; D000097768:Retinoic Acid Receptor gamma
chemical_list: D004268:DNA-Binding Proteins; D000090062:Kruppel-Like Factor 4; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D057093:Orphan Nuclear Receptors; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D049230:Retinoid X Receptor beta; D000097768:Retinoic Acid Receptor gamma; C000715467:KLF4 protein, human; C539821:NR4A1 protein, human; C539882:NR4A2 protein, human; C490412:NR4A3 protein, human