ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2.
- Authors
- Girgenti, Matthew J; LoTurco, Joseph J; Maher, Brady J
- Year
- 2012
- Journal
- PloS one
- PMID
- 22384243
- DOI
- 10.1371/journal.pone.0032404
- PMCID
- PMC3288100
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.
Recombinant and endogenous ZNF804a is localized to the nucleus of neural progenitor cells. A) pCAG-ZNF804A was transfected into rat neural progenitor cells for twenty-four hours and processed for immunocytochemistry with antibodies against an myc-tag fused to ZNF804a. Expression of ZNF804a co-localizes with the nuclear counter stain DAPI (Scale bar = 10 Β΅m). B) Immunohistochemistry using anti-ZNF804a antibodies showing endogenous ZNF804a protein (left panel) co-localizes (right panel) with the nuclear counter stain TOPRO (middle panel) in E11 neural progenitor cells within the ventricle zone. C) Endogenous ZNF804a protein is devoid of the cytoplasmic fraction and observed in the nuclear fraction. As a control to demonstrate proper cellular fractionation, Nestin, a cytoplasmic marker of neural progenitor cells, is observed in the cytoplasmic fraction. Likewise, Histone H3, a chromatin marker, is observed in the nuclear fraction.
ZNF804a regulates the transcription of several Schizophrenia- associated genes. A) Quantitative RT-PCR was performed on 37 SZ associated gene transcripts following ZNF804A transfection. PRSS16 and COMT (red) showed robust upregulation of transcription twenty-four hours after transfection (Bonferroni corrected p<0.05; n = 5). Conversely, PDE4B and DRD2 (green) transcript levels were downregulated following ZNF804a transfection (Bonferroni corrected p<0.05; n = 5).
Recombinant ZNF804a binds to the DNA regions directly upstream of the transcription start site of PRSS16 and COMT. A) Chromatin was immunoprecipitated with antibody directed against the myc-tag or IgG as control and then probed with anti-ZNF804a antibody. Recombinant ZNF804a was correctly identified by anti-ZNF804a antibody. BβC) Tiling qRT-PCR of the promoter sequences of PRSS16 and COMT following ChIP against the myc-tag reveals enrichment for ZNF804A. Enrichment of ZNF804A on the PRSS16 promoter appears 1.5 Kb 5β² upstream of the transcription start sites (TSS) while enrichment on the COMT promoter appears 1 Kb 5β² upstream of the TSS D) Tiling qRT-PCR of the promoter sequences of DRD2 and PDE4B following ChiP did not result in enrichment of ZNF804a (all figures *p<0.05, Students t-test, Error bars indicate Β± SEM).
Endogenous ZNF804a binds to the DNA regions directly upstream of the transcription start site of PRSS16 and COMT. A) Tiling qRT-PCR of the promoter sequences of PRSS16 and COMT following ChIP using anti-ZNF804a reveals enrichment for ZNF804A. Enrichment of ZNF804A on the PRSS16 promoter appears 1.5 Kb 5β² upstream of the transcription start sites (TSS) while enrichment on the COMT promoter appears 1 Kb 5β² upstream of the TSS.
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| 20 | Materials and Methods β Chromatin Immunoprecipitation | Chromatin immunoprecipitations were performed as described with several modifications (below).β¦ |
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| Heterogeneity and individuality: microRNAs in mental disorders. | Hommers LG et al. | β | 2015 | β |
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| Recent genetic findings in schizophrenia and their therapeutic relevance. | Harrison PJ | β | 2015 | β |
| Replication of ZNF804A gene variant associations with risk of heroin addiction. | Hancock DB et al. | β | 2015 | β |
| The current and potential impact of genetics and genomics on neuropsychopharmacology. | Harrison PJ | β | 2015 | β |
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| What is the impact of genome-wide supported risk variants for schizophrenia and bipolar disorder on brain structure and function? A systematic review. | Gurung R et al. | β | 2015 | β |
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| Allelic imbalance associated with the schizophrenia risk SNP rs1344706 indicates a cis-acting variant in ZNF804A. | Guella I et al. | β | 2014 | β |
| Analysis of schizophrenia-related genes and electrophysiological measures reveals ZNF804A association with amplitude of P300b elicited by novel sounds. | Del Re EC et al. | β | 2014 | β |
| Expression of ZNF804A in human brain and alterations in schizophrenia, bipolar disorder, and major depressive disorder: a novel transcript fetally regulated by the psychosis risk variant rs1344706. | Tao R et al. | β | 2014 | β |
| Further evidence for the impact of a genome-wide-supported psychosis risk variant in ZNF804A on the Theory of Mind Network. | Mohnke S et al. | β | 2014 | β |
| How might ZNF804A variants influence risk for schizophrenia and bipolar disorder? A literature review, synthesis, and bioinformatic analysis. | Hess JL et al. | β | 2014 | β |
| Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences. | Colonna V et al. | β | 2014 | β |
| Human genomic regions with exceptionally high or low levels of population differentiation identified from 911 whole-genome sequences | Colonna V et al. | β | 2014 | β |
| MicroRNA-9 and microRNA-326 regulate human dopamine D2 receptor expression, and the microRNA-mediated expression regulation is altered by a genetic variant. | Shi S et al. | β | 2014 | β |
| miR-137: a new player in schizophrenia. | Yin J et al. | β | 2014 | β |
| Prefronto-striatal physiology is associated with schizotypy and is modulated by a functional variant of DRD2. | Taurisano P et al. | β | 2014 | β |
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| Zinc finger protein 804A (ZNF804A) and verbal deficits in individuals with autism. | Anitha A et al. | β | 2014 | β |
| Genetics of schizophrenia: What do we know? | Zhang JP et al. | β | 2013 | β |
| Potential roles of zinc in the pathophysiology and treatment of major depressive disorder. | Swardfager W et al. | β | 2013 | β |
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| ZNF804A genotype modulates neural activity during working memory for faces. | Linden DE et al. | β | 2013 | β |
| Experimental validation of candidate schizophrenia gene ZNF804A as target for hsa-miR-137. | Kim AH et al. | β | 2012 | β |
| ZNF804A rs1344706 variant and schizophrenia in a Romanian population from Cluj Napoca. | Zaharie A et al. | β | 2012 | β |