1. ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2
- Author
-
Brady J. Maher, Matthew J. Girgenti, and Joseph J. LoTurco
- Subjects
Transcription, Genetic ,Gene Expression ,lcsh:Medicine ,0302 clinical medicine ,Gene expression ,Molecular Cell Biology ,Transcriptional regulation ,lcsh:Science ,Regulation of gene expression ,Psychiatry ,0303 health sciences ,Multidisciplinary ,Chromosome Biology ,Stem Cells ,Serine Endopeptidases ,Animal Models ,Immunohistochemistry ,Recombinant Proteins ,Chromatin ,Mental Health ,Medicine ,Research Article ,Kruppel-Like Transcription Factors ,Biology ,Catechol O-Methyltransferase ,03 medical and health sciences ,Model Organisms ,Genetics ,Animals ,Humans ,Genetic Predisposition to Disease ,Gene ,030304 developmental biology ,Cell Nucleus ,Catechol-O-methyl transferase ,Binding Sites ,Receptors, Dopamine D2 ,Gene Expression Profiling ,lcsh:R ,Promoter ,Molecular biology ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Rats ,Gene Expression Regulation ,Schizophrenia ,lcsh:Q ,Chromatin immunoprecipitation ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Neuroscience - 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.
- Published
- 2012