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.
Highlights
Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease with complicated clinical manifestations and high mortality, and is associated with development of autoantibodies and inflammatory responses resulting in damage to multiple organs and systems (Tsokos et al, 2016)
Compared with that in healthy controls (HCs), the expression level of acetyltransferase N-acetyltransferase 10 (NAT10) was markedly decreased in CD4+ T cells from systemic lupus erythematosus (SLE) patients (P < 0.001; Figure 1D)
These results suggested that NAT10 expression might be associated with the alternation of global ac4C levels in SLE
Summary
Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease with complicated clinical manifestations and high mortality, and is associated with development of autoantibodies and inflammatory responses resulting in damage to multiple organs and systems (Tsokos et al, 2016). Accumulating evidence indicates that the pathogenesis and etiology of this systemic disease are highly intricate, being influenced by several factors including genetic susceptibility, sex hormones, environmental risk factors, and immunological mechanisms (Rönnblom and Elkon, 2010; Liu and Davidson, 2012; Tsokos et al, 2016). Of these factors, imbalanced innate and adaptive immune responses, including immune cells (CD4+ T cells, B cells, and Th17 cells), cytokines (type I interferon and interleukin) and complement proteins contribute to inflammatory processes and tissue injury (Morel, 2017; Song et al, 2020). We identified novel aberrant mRNA modification, 5-methylcytidine (m5C), linked to critical immune pathways in lupus CD4+ T cells (Guo et al, 2020)
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