ZNF804a Regulates Expression of the Schizophrenia-Associated Genes PRSS16, COMT, PDE4B, and DRD2

Abstract

ZNF804a was identified by a genome-wide association study (GWAS) in which a single nucleotide polymorphism (SNP rs1344706) in ZNF804a reached genome-wide statistical significance for association with a combined diagnosis of schizophrenia (SZ) and bipolar disorder. Although the molecular function of ZNF804a is unknown, the amino acid sequence is predicted to contain a C2H2-type zinc-finger domain and suggests ZNF804a plays a role in DNA binding and transcription. Here, we confirm that ZNF804a directly contributes to transcriptional control by regulating the expression of several SZ associated genes and directly interacts with chromatin proximal to the promoter regions of PRSS16 and COMT, the two genes we find upregulated by ZNF804a. Using immunochemistry we establish that ZNF804a is localized to the nucleus of rat neural progenitor cells in culture and in vivo. We demonstrate that expression of ZNF804a results in a significant increase in transcript levels of PRSS16 and COMT, relative to GFP transfected controls, and a statistically significant decrease in transcript levels of PDE4B and DRD2. Furthermore, we show using chromatin immunoprecipitation assays (ChIP) that both epitope-tagged and endogenous ZNF804a directly interacts with the promoter regions of PRSS16 and COMT, suggesting a direct upregulation of transcription by ZNF804a on the expression of these genes. These results are the first to confirm that ZNF804a regulates transcription levels of four SZ associated genes, and binds to chromatin proximal to promoters of two SZ genes. These results suggest a model where ZNF804a may modulate a transcriptional network of SZ associated genes.

MicroRNA-9 and MicroRNA-326 Regulate Human Dopamine D2 Receptor Expression, and the MicroRNA-mediated Expression Regulation Is Altered by a Genetic Variant

“…For instance, one of the expression repressors of miR-9, nuclear receptor subfamily 2 group E member 1 (NR2E1; also known as TLX) (71), is a target of miR-137 (72), the latter being one of the most strongly SZassociated loci (69). Moreover, another genome-wide association study-implicated SZ susceptibility gene, ZNF804A, is a target of miR-137 (69,73,74) and also regulates transcription of DRD2 (75). We 3 and others (76) have shown that the SZ risk allele of MIR137 locus likely reduces MIR137 expression.…”

Association between variants of zinc finger genes and psychiatric disorders: Systematic review and meta-analysis

“…However, because there is no conclusive evidence of the neurobiological function of ZNF804A, we could only speculate the possible biological contribution of this gene from the existing related studies. First, previous studies showed ZNF804A regulates the transcript levels of dopamine D 2 receptors (DRD2) and catechol-Omethyltransferase (COMT), which are involved in dopaminergic neurotransmission (Girgenti et al, 2012). It may also alter the expression of other genes in the dopamine system, such as the genes for D 1 , D 3 , and D 4 receptors (Kanahara et al, 2013;Miyake et al, 2011).…”

“…Downstream, ZNF804A is involved in encoding transcription regulators of the SMARCA2 gene, the down regulation of which generates abnormal dendritic spine morphology that is an intermediate phenotype of schizophrenia (Loe-Mie et al, 2010). Other reports show that ZNF804A directly contributes to transcriptional control by regulating the expression of several schizophrenia-associated genes, such as PRSS16 and COMT (Girgenti et al, 2012). ZNF804A knockdown also affects the expression of genes involved in cell adhesion, suggesting its role in such processes as neural migration, neurite outgrowth, and synapse formation .…”

Further Evidence for the Impact of a Genome-Wide-Supported Psychosis Risk Variant in ZNF804A on the Theory of Mind Network

“…In line with this, Hill and Bray (2012) found evidence that the risk SNP exerts effects on ZNF804A allelic expression at a fetal stage of brain development. Furthermore, first results suggest a role in the regulation of expression of other genes associated with schizophrenia (Girgenti et al, 2012) as well as genes involved in cell adhesion (Hill et al, 2011).…”