Interactome analysis reveals ZNF804A, a schizophrenia risk gene, as a novel component of protein translational machinery critical for embryonic neurodevelopment

Abstract

Recent genome-wide association studies identified over 100 genetic loci that significantly associate with schizophrenia (SZ). A top candidate gene, ZNF804A, was robustly replicated in different populations. However, its neural functions are largely unknown. Here we show in mouse that ZFP804A, the homolog of ZNF804A, is required for normal progenitor proliferation and neuronal migration. Using a yeast two-hybrid genome-wide screen, we identified novel interacting proteins of ZNF804A. Rather than transcriptional factors, genes involved in mRNA translation are highly represented in our interactome result. ZNF804A co-fractionates with translational machinery and modulates the translational efficiency as well as the mTOR pathway. The ribosomal protein RPSA interacts with ZNF804A and rescues the migration and translational defects caused by ZNF804A knockdown. RNA immunoprecipitation–RNAseq (RIP-Seq) identified transcripts bound to ZFP804A. Consistently, ZFP804A associates with many short transcripts involved in translational and mitochondrial regulation. Moreover, among the transcripts associated with ZFP804A, a SZ risk gene, neurogranin (NRGN), is one of ZFP804A targets. Interestingly, downregulation of ZFP804A decreases NRGN expression and overexpression of NRGN can ameliorate ZFP804A-mediated migration defect. To verify the downstream targets of ZNF804A, a Duolink in situ interaction assay confirmed genes from our RIP-Seq data as the ZNF804A targets. Thus, our work uncovered a novel mechanistic link of a SZ risk gene to neurodevelopment and translational control. The interactome-driven approach here is an effective way for translating genome-wide association findings into novel biological insights of human diseases.

Schizophrenia‑associated microRNA‑148b‑3p regulates COMT and PRSS16 expression by targeting the ZNF804A gene in human neuroblastoma cells

“…While the precise function of ZNF804A is unknown in psychiatric disorders, the biological function and molecular mechanisms of ZNF804A have been revealed by previous studies (25,26). Furthermore, the neuronal function and molecular mechanisms of ZNF804A have been revealed by two landmark studies (25,26).…”

“…using neurons derived from human neural progenitor cells (nPcs), human induced pluripotent stem cells or primary rat cortical neurons, deans et al (25) revealed that ZnF804a localizes to synapses, and regulates neurite formation and dendritic spine structure. in addition, Zhou et al (26) revealed that the rodent homologue of ZNF804A (Zfp804a) is required for nPc proliferation and neuronal migration, and also identified a novel role of ZNF804A in modulating protein translational efficiency during neurodevelopment.…”

Dopamine perturbation of gene co-expression networks reveals differential response in schizophrenia for translational machinery

“…In contrast, for human olfactory neurosphere-derived cells, discovery-based proteomics and functional analyses revealed significant reductions in particular ribosomal proteins among SZ patients, including total ribosomal signal intensity 53 . And, perhaps most intriguingly, Zhou et al 54 . reveal that the interactome of ZNF804A , a SZ risk gene robustly replicated in different populations 55–58 , is highly represented by ribosomal and mitochondrial proteins, with ZNF804A modulating translational efficiency.…”

The Biomarker and Therapeutic Potential of Circular Rnas in Schizophrenia

“…The zinc finger protein 804A ( ZNF804A ) gene is broadly expressed in brain tissues and has been suggested to be one of the possible SZ risk factors [ 100 ]. ZNF804A has DNA, RNA, and protein binding ability and acts as a regulator of gene expression [ 101 , 102 ]. Several GWASs have shown that mutations in this gene had a strong association with SZ [ 103 , 104 ].…”