Epitranscriptomic N4-Acetylcytidine Profiling in CD4+ T Cells of Systemic Lupus Erythematosus

Gangqiang Guo; Xinyu Shi; Huijing Wang; Lele Ye; Xinya Tong; Kejing Yan; Ning Ding; Chaosheng Chen; Huidi Zhang; Xiangyang Xue

doi:10.3389/fcell.2020.00842

Epitranscriptomic N4-Acetylcytidine Profiling in CD4⁺ T Cells of Systemic Lupus Erythematosus

Front Cell Dev Biol. 2020 Aug 28:8:842. doi: 10.3389/fcell.2020.00842. eCollection 2020.

Authors

Gangqiang Guo^{1

2}, Xinyu Shi², Huijing Wang³, Lele Ye^{2

4}, Xinya Tong², Kejing Yan², Ning Ding², Chaosheng Chen⁵, Huidi Zhang⁵, Xiangyang Xue²

Affiliations

¹ School of Life Sciences and Technology, Tongji University, Shanghai, China.
² Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
³ Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
⁴ Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁵ Department of Nephrology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.

Abstract

The emerging epitranscriptome plays an essential role in autoimmune disease. As a novel mRNA modification, N4-acetylcytidine (ac⁴C) could promote mRNA stability and translational efficiency. However, whether epigenetic mechanisms of RNA ac⁴C 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 ac⁴C 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 ac⁴C profile in CD4⁺ T cells of SLE patients by ac⁴C-RIP-Seq and found ac⁴C distribution in mRNA transcripts to be highly conserved and enriched in mRNA coding sequence regions. Using bioinformatics analysis, the 3879 and 4073 ac⁴C 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-κB signaling. Moreover, we demonstrated the ac⁴C-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 ac⁴C-related transcripts, including USP18, GPX1, and RGL1, regulate mRNA catabolic processes and translational initiation. Our study identified novel dysregulated ac⁴C 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 ac⁴C modifications in SLE pathogenesis.

Keywords: CD4+ T cells; N4-acetylcytidine (ac4C); NAT10; epitranscriptome; systemic lupus erythematosus.