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.

中文翻译：

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相互作用分析表明，精神分裂症风险基因ZNF804A是对胚胎神经发育至关重要的蛋白质翻译机制的新组成部分。

最近的全基因组关联研究确定了100多个与精神分裂症（SZ）显着相关的遗传基因座。顶级候选基因ZNF804A在不同人群中得到了强大的复制。但是，其神经功能在很大程度上是未知的。在这里，我们在小鼠中显示ZFP804A（ZNF804A的同源物）是正常祖细胞增殖和神经元迁移所必需的。使用酵母双杂交全基因组筛选，我们确定了ZNF804A的新型相互作用蛋白。在我们的相互作用组结果中，mRNA翻译中涉及的基因比转录因子更重要。ZNF804A与翻译机器共同分离并调节翻译效率以及mTOR途径。核糖体蛋白RPSA与ZNF804A相互作用，挽救了ZNF804A敲低引起的迁移和翻译缺陷。RNA免疫沉淀-RNAseq（RIP-Seq）鉴定了与ZFP804A结合的转录本。一致地，ZFP804A与参与翻译和线粒体调控的许多短转录本相关。此外，在与ZFP804A相关的转录本中，SZ风险基因神经颗粒（NRGN）是ZFP804A的靶标之一。有趣的是，ZFP804A的下调降低了NRGN的表达，NRGN的过表达可以改善ZFP804A介导的迁移缺陷。为了验证ZNF804A的下游靶标，Duolink原位相互作用测定从我们的RIP-Seq数据中确认了基因为ZNF804A靶标。因此，我们的工作揭示了SZ风险基因与神经发育和翻译控制的新型机制联系。