SAFA facilitates chromatin opening of immune genes through interacting with anti-viral host RNAs.
SAFA facilitates chromatin opening of immune genes through interacting with anti-viral host RNAs.
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SAFA 通过与抗病毒宿主 RNA 相互作用促进免疫基因染色质打开
DOI：
10.1371/journal.ppat.1010599
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发表时间：
2022-06
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
染色质结构和可及性的调控决定了基因的转录活性，从而赋予宿主特定功能的基因表达模式。在病毒感染时，先天免疫反应提供第一道防线，允许快速生产各种抗病毒细胞因子。在宿主防御病毒感染的过程中，染色质可及性是如何调控的，这方面的知识仍然有限。我们的前期工作发现核基质蛋白SAFA监测病毒RNA并调节抗病毒免疫基因的表达。然而，SAFA如何调节抗病毒免疫基因的特异性诱导仍然未知。在这里，通过RNA-seq、ATAC-seq和ChIP-seq检测的整合，我们发现SAFA的缺失特异性地降低了病毒诱导基因的染色质可及性、激活和表达。突变实验表明，SAFA的rna结合能力对其调节抗病毒染色质可及性的功能至关重要。RIP-seq结果显示，病毒感染后，SAFA只与抗病毒相关rna结合。进一步，我们将CRISPR-Cas13d介导的RNA敲低系统与ATAC-qPCR相结合，证明SAFA与相应抗病毒RNA的结合特异性地介导了相应染色质的开放和抗病毒基因的稳健转录。此外，这些相关rna的敲低以核外信号通路依赖的方式抑制了相关基因的可及性。有趣的是，VSV感染在c端切割SAFA蛋白，从而剥夺了其免疫逃避的RNA结合能力。因此，我们的研究结果表明，SAFA和相互作用的RNA产物协同作用，重塑染色质可及性，促进抗病毒先天免疫反应。染色质开放和基因表达的调控是宿主防御病毒感染的一个关键环节，它赋予宿主及时有效的抗病毒基因表达模式。我们以前报道过核基质蛋白SAFA监测病毒RNA并调节抗病毒免疫基因的表达。然而，SAFA如何调节抗病毒免疫基因的表达以及是什么决定了抗病毒免疫基因的特异性诱导尚不清楚。在这里，我们使用了高通量测序技术的组合，发现SAFA和相互作用的RNA产物协同并特异性地重塑了染色质的可及性，以促进抗病毒免疫基因的表达。我们还发现VSV感染在c端切割SAFA蛋白并剥夺其RNA结合能力以逃避免疫。我们的研究为染色质重塑促进抗病毒免疫基因诱导的机制提供了新的见解。
Regulation of chromatin structure and accessibility determines the transcription activities of genes, which endows the host with function-specific patterns of gene expression. Upon viral infection, the innate immune responses provide the first line of defense, allowing rapid production of variegated antiviral cytokines. Knowledge on how chromatin accessibility is regulated during host defense against viral infection remains limited. Our previous work found that the nuclear matrix protein SAFA surveilled viral RNA and regulated antiviral immune genes expression. However, how SAFA regulates the specific induction of antiviral immune genes remains unknown. Here, through integration of RNA-seq, ATAC-seq and ChIP-seq assays, we found that the depletion of SAFA specifically decreased the chromatin accessibility, activation and expression of virus induced genes. And mutation assays suggested that the RNA-binding ability of SAFA was essential for its function in regulating antiviral chromatin accessibility. RIP-seq results showed that SAFA exclusively bound with antiviral related RNAs following viral infection. Further, we combined the CRISPR-Cas13d mediated RNA knockdown system with ATAC-qPCR, and demonstrated that the binding between SAFA and according antiviral RNAs specifically mediated the openness of the corresponding chromatin and following robust transcription of antiviral genes. Moreover, knockdown of these associated RNAs dampened the accessibility of related genes in an extranuclear signaling pathway dependent manner. Interestingly, VSV infection cleaved SAFA protein at the C-terminus which deprived its RNA binding ability for immune evasion. Thus, our results demonstrated that SAFA and the interacting RNA products collaborated and remodeled chromatin accessibility to facilitate antiviral innate immune responses. Regulation of chromatin opening and gene expression underlies a key point during host defense against viral infection, which endows the host with timely and effective antiviral gene expression patterns. We previously reported that the nuclear matrix protein SAFA surveils viral RNA and regulates antiviral immune genes expression. However, how SAFA regulates the expression and what determines the specific induction of antiviral immune genes remains unclear. Here, we used a combination of high-throughput sequencing technologies and found that SAFA and the interacting RNA products collaborated and specifically remodeled chromatin accessibility to facilitate antiviral immune genes expression. We also found that VSV infection cleaved SAFA protein at the C-terminus and deprived its RNA binding ability for immune evasion. Our study provides new insights into the mechanism by which chromatin remodeling facilitates the induction of antiviral immune genes.
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