PDF(Pubmed)
Abstract：
BACKGROUND: RNA editing is a process that increases transcriptome diversity, often through Adenosine Deaminases Acting on RNA (ADARs) that catalyze the deamination of adenosine to inosine. ADAR editing plays an important role in regulating brain function and immune activation, and is dynamically regulated during brain development. Additionally, the ADAR1 p150 isoform is induced by interferons in viral infection and plays a role in antiviral immune response. However, the question of how virus-induced ADAR expression affects host transcriptome editing remains largely unanswered. This question is particularly relevant in the context of congenital infections, given the dynamic regulation of ADAR editing during brain development, the importance of this editing for brain function, and subsequent neurological symptoms of such infections, including microcephaly, sensory issues, and other neurodevelopmental abnormalities. Here, we begin to address this question, examining ADAR expression in publicly available datasets of congenital infections of human cytomegalovirus (HCMV) microarray expression data, as well as mouse cytomegalovirus (MCMV) and mouse/ human induced pluripotent neuroprogenitor stem cell (hiNPC) Zika virus (ZIKV) RNA-seq data.
RESULTS: We found that in all three datasets, ADAR1 was overexpressed in infected samples compared to uninfected samples. In the RNA-seq datasets, editing rates were also analyzed. In all mouse infections cases, the number of editing sites was significantly increased in infected samples, albeit this was not the case for hiNPC ZIKV samples. Mouse ZIKV samples showed altered editing of well-established protein-recoding sites such as Gria3, Grik5, and Nova1, as well as editing sites that may impact miRNA binding.
CONCLUSIONS: Our findings provide evidence for changes in ADAR expression and subsequent dysregulation of ADAR editing of host transcriptomes in congenital infections. These changes in editing patterns of key neural genes have potential significance in the development of neurological symptoms, thus contributing to neurodevelopmental abnormalities. Further experiments should be performed to explore the full range of editing changes that occur in different congenital infections, and to confirm the specific functional consequences of these editing changes.
RESULTS: We found that in all three datasets, ADAR1 was overexpressed in infected samples compared to uninfected samples. In the RNA-seq datasets, editing rates were also analyzed. In all mouse infections cases, the number of editing sites was significantly increased in infected samples, albeit this was not the case for hiNPC ZIKV samples. Mouse ZIKV samples showed altered editing of well-established protein-recoding sites such as Gria3, Grik5, and Nova1, as well as editing sites that may impact miRNA binding.
CONCLUSIONS: Our findings provide evidence for changes in ADAR expression and subsequent dysregulation of ADAR editing of host transcriptomes in congenital infections. These changes in editing patterns of key neural genes have potential significance in the development of neurological symptoms, thus contributing to neurodevelopmental abnormalities. Further experiments should be performed to explore the full range of editing changes that occur in different congenital infections, and to confirm the specific functional consequences of these editing changes.
摘要：
背景：RNA编辑是一个增加转录组多样性的过程，通常通过腺苷脱氨酶作用于RNA（ADARs），催化腺苷脱氨为肌苷。ADAR编辑在调节脑功能和免疫激活方面发挥重要作用,并在大脑发育过程中动态调节。此外,ADAR1p150亚型在病毒感染中由干扰素诱导，并在抗病毒免疫应答中起作用。然而,病毒诱导的ADAR表达如何影响宿主转录组编辑的问题在很大程度上仍未得到解答.这个问题在先天性感染的背景下尤其相关，考虑到ADAR编辑在大脑发育过程中的动态调节，这种编辑对大脑功能的重要性，以及这种感染的神经系统症状，包括小头畸形,感官问题，和其他神经发育异常。这里,我们开始解决这个问题，在人类巨细胞病毒（HCMV）微阵列表达数据的先天性感染的公开数据集中检查ADAR表达，以及小鼠巨细胞病毒（MCMV）和小鼠/人诱导多能神经祖细胞（hiNPC）寨卡病毒（ZIKV）RNA-seq数据。
结果：我们发现在所有三个数据集中，与未感染样品相比,ADAR1在感染样品中过表达。在RNA-seq数据集中，编辑率也进行了分析。在所有小鼠感染病例中，受感染样本的编辑网站数量显着增加，尽管对于hiNPCZIKV样本并非如此。小鼠ZIKV样品显示对已建立的蛋白质重新编码位点(如Gria3、Grik5和Nova1)以及可能影响miRNA结合的编辑位点的编辑改变。
结论：我们的发现为先天性感染中宿主转录组的ADAR表达和随后的ADAR编辑失调提供了证据。这些关键神经基因编辑模式的变化对神经症状的发展具有潜在的意义，从而导致神经发育异常。应进行进一步的实验，以探索在不同先天性感染中发生的全方位编辑变化，并确认这些编辑更改的特定功能后果。
结果：我们发现在所有三个数据集中，与未感染样品相比,ADAR1在感染样品中过表达。在RNA-seq数据集中，编辑率也进行了分析。在所有小鼠感染病例中，受感染样本的编辑网站数量显着增加，尽管对于hiNPCZIKV样本并非如此。小鼠ZIKV样品显示对已建立的蛋白质重新编码位点(如Gria3、Grik5和Nova1)以及可能影响miRNA结合的编辑位点的编辑改变。
结论：我们的发现为先天性感染中宿主转录组的ADAR表达和随后的ADAR编辑失调提供了证据。这些关键神经基因编辑模式的变化对神经症状的发展具有潜在的意义，从而导致神经发育异常。应进行进一步的实验，以探索在不同先天性感染中发生的全方位编辑变化，并确认这些编辑更改的特定功能后果。
