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.
Highlights
Schizophrenia (SZ) is a heritable disorder having no single gene or environmental factor that accounts for a majority of cases
We assayed transcript levels in neural progenitors isolated from rat forebrain at embryonic day 11 (E11)
These results suggest endogenous ZNF804a is localized in the nucleus of neural progenitor cells both in vitro and in vivo, and our recombinant ZNF804a expression construct has a similar localization pattern to that observed for endogenous ZNF804a protein
Summary
Schizophrenia (SZ) is a heritable disorder having no single gene or environmental factor that accounts for a majority of cases. We hypothesize that transcription factors associated with SZ may be central to a transcriptional network that regulates the expression of other SZ associated genes. Genome-wide association studies (GWAS) are a powerful method to identify single nucleotide polymorphisms (SNPs) that are associated with a diagnosis. The first gene to reach genomewide significance for psychosis was ZNF804a when SNP rs1344706 was significantly associated when schizophrenia and bipolar disorder diagnoses are combined [3]. Several follow up GWAS studies have replicated the association of rs1344706 with SZ in different populations [4,5,6], and several other SNPs near the ZNF804a locus have a significant association with SZ [7,8]
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