Modulation of host gene expression by the zinc finger antiviral protein [RNA-seq]

The zinc finger antiviral protein (ZAP) depletes non-self RNAs through recognition of their elevated CpG dinucleotide content. CpG dinucleotides are sparse in most endogenous mammalian mRNAs, but a subset might potentially be modulated by ZAP. While CpG frequency alone is insufficient to predict ZAP-regulation, we developed an algorithm using experimentally determined compositional features to predict which endogenous mRNAs may be ZAP-regulated. Using ZAP-knockout mice, we demonstrate that levels of many host mRNAs that are algorithmically predicted ZAP targets are indeed increased when ZAP is absent. ZAP is interferon-inducibel and we also identify genes that are downregulated by ZAP during an innate immune response. Many ZAP-regulated gene products are extracellular matrix or of nucleosome components, whose ZAP mediated control is conserved in human cells. Overall, we provide a new tool for the prediction of ZAP target genes and reveal host mRNAs that are ZAP-regulated. To evaluate the effects of ZAP on endogenous gene expression, we have (1) generated ZAP-knockout mice, (2) treated ZAP+/+ and ZAP-/- mice with poly I:C, (3) extracted spleens at 6, 12, and 24h post-treatment, and (4) extracted total RNA from spleens and performed RNA sequencing.