Epitranscriptomic N4-Acetylcytidine Profiling in CD4+T Cells of Systemic Lupus Erythematosus
Epitranscriptomic N4-Acetylcytidine Profiling in CD4+T Cells of Systemic Lupus Erythematosus
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DOI：
10.3389/fcell.2020.00842
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发表时间：
2020-08-28
影响因子：
5.5
通讯作者：
Xue, Xiangyang
中科院分区：
文献类型：
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作者：
Guo, Gangqiang;Shi, Xinyu;Xue, Xiangyang
新出现的表位转录组在自身免疫性疾病中起着至关重要的作用。N4-乙酰胞苷(Ac(4)C)作为一种新的信使核糖核酸修饰方法，可以提高信使核糖核酸的稳定性和翻译效率。然而，RNAac(4)C修饰的表观遗传学机制是否参与系统性红斑狼疮(SLE)仍不清楚。在此，我们使用质谱仪(LC-MS/MS)检测了SLE患者CD4(+)T细胞中的11种修饰。此外，使用来自四个CD4(+)T细胞库的样本，我们发现与健康对照组(HCS)相比，SLE患者ac(4)C mRNA的修饰较低。同时，RT-qPCR检测到狼疮患者CD4(+)T细胞中乙酰基转移酶NAT10的表达显著降低。然后，我们用Ac(4)C-RIP-Seq分析了SLE患者CD4(+)T细胞中Ac(4)C的转录组分布，发现Ac(4)C在转录本中的分布是高度保守的，并且在mRNA编码序列区域丰富。生物信息学分析发现，分别在SLE样本中发现的3879和4073Ac(4)C高乙酰化和低乙酰化峰显著参与了SLE相关的功能丰富，包括多种代谢和转录相关过程、ROS诱导的细胞信号、细胞凋亡信号和核因子-kappaB信号。此外，我们还展示了Ac(4)C修饰的狼疮CD4(+)T细胞的基因生物学功能调节网络。值得注意的是，我们确定了26个高乙酰化上调的基因在自身免疫性疾病和疾病相关过程中发挥了重要作用。此外，独特的Ac(4)C相关转录本，包括USP18、GPX1和RGL1，调节mRNA的分解代谢过程和翻译启动。我们的研究发现了与关键免疫和炎症反应相关的新的失调的ac(4)C mRNAs，它们在狼疮CD4(+)T细胞中具有翻译潜力。因此，我们的发现揭示了mRNA Ac(4)C修饰在SLE发病机制中的转录意义和潜在的治疗靶点。
The emerging epitranscriptome plays an essential role in autoimmune disease. As a novel mRNA modification, N4-acetylcytidine (ac(4)C) could promote mRNA stability and translational efficiency. However, whether epigenetic mechanisms of RNA ac(4)C modification are involved in systemic lupus erythematosus (SLE) remains unclear. Herein, we detected eleven modifications in CD4(+)T cells of SLE patients using mass spectrometry (LC-MS/MS). Furthermore, using samples from four CD4(+)T cell pools, we identified lower modification of ac(4)C mRNA in SLE patients as compared to that in healthy controls (HCs). Meanwhile, significantly lower mRNA acetyltransferase NAT10 expression was detected in lupus CD4(+)T cells by RT-qPCR. We then illustrated the transcriptome-wide ac(4)C profile in CD4(+)T cells of SLE patients by ac(4)C-RIP-Seq and found ac(4)C distribution in mRNA transcripts to be highly conserved and enriched in mRNA coding sequence regions. Using bioinformatics analysis, the 3879 and 4073 ac(4)C hyper-acetylated and hypoacetylated peaks found in SLE samples, respectively, were found to be significantly involved in SLE-related function enrichments, including multiple metabolic and transcription-related processes, ROS-induced cellular signaling, apoptosis signaling, and NF-kappa B signaling. Moreover, we demonstrated the ac(4)C-modified regulatory network of gene biological functions in lupus CD4(+)T cells. Notably, we determined that the 26 upregulated genes with hyperacetylation played essential roles in autoimmune diseases and disease-related processes. Additionally, the unique ac(4)C-related transcripts, includingUSP18,GPX1, andRGL1, regulate mRNA catabolic processes and translational initiation. Our study identified novel dysregulated ac(4)C mRNAs associated with critical immune and inflammatory responses, that have translational potential in lupus CD4(+)T cells. Hence, our findings reveal transcriptional significance and potential therapeutic targets of mRNA ac(4)C modifications in SLE pathogenesis.