Dataset Information

[Effect of aberrant H3K27me3 modification in promoter regions on cAMP response element modulator ? expression in CD4+ T cells from patients with systemic lupus erythematosus].

ABSTRACT: OBJECTIVE:Increased cAMP response element modulator ? (CREM?) in T cells plays an essential role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the mechanisms that elevates CREM? expression in SLE. METHODS:CD4+ T cells from 5 healthy volunteers and 5 SLE patients were isolated for analysis of histone H3 lysine 27 trimethylation (H3K27me3) enrichment in different gene promoters using chromatin immunoprecipitation (ChIP) microarray. The levels of H3K27me3, H3K27 demethylases Jumonji domain containing 3 (JMJD3) and ubiquitously transcribed X (UTX), and H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) within the CREM? promoter were subsequently tested by ChIP and real?time PCR in CD4+ T cells from 30 normal controls and 30 SLE patients; CREM? mRNA level was also determined by real?time RT?PCR. RESULTS:Analysis of ChIP microarray data identified that H3K27me3 enrichment at the CREM? promoter in CD4+ T cells from SLE patients was 0.23 times that of the normal control subjects. The results of ChIP and real?time PCR confirmed a marked decrease of H3K27me3 enrichment at the CREM? promoter in CD4+ T cells from SLE patients (P<0.001). The level of H3K27me3 at the promoter was negatively correlated with CREM? mRNA level in CD4+ T cells from SLE patients (P<0.001). In addition, a sharp increase was observed in JMJD3 binding at the CREM? promoter region in CD4+ T cells from SLE patients (P<0.001), and it was negatively correlated with H3K27me3 enrichment (P<0.001) and positively correlated with CREM? mRNA level (P<0.001). There were no significant changes in UTX (P=0.172) or EZH2 (P=0.281) binding at the CREM? promoter region in CD4+ T cells from SLE patients as compared to normal controls. CONCLUSION:Increased JMJD3 binding down-regulates H3K27me3 enrichment at the CREM? promoter in CD4+ T cells of SLE patients to stimulate CREM? overexpression and result in the development of SLE.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC6744012 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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[Effect of aberrant H3K27me3 modification in promoter regions on cAMP response element modulator α expression in CD4<sup>+</sup> T cells from patients with systemic lupus erythematosus].

Zhang Qing Q Ding Shu S Zhang Hui-Lin HL

Nan fang yi ke da xue xue bao = Journal of Southern Medical University 20171201 12

<h4>Objective</h4>Increased cAMP response element modulator α (CREMα) in T cells plays an essential role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the mechanisms that elevates CREMα expression in SLE.<h4>Methods</h4>CD4<sup>+</sup> T cells from 5 healthy volunteers and 5 SLE patients were isolated for analysis of histone H3 lysine 27 trimethylation (H3K27me3) enrichment in different gene promoters using chromatin immunoprecipitation (ChIP ...[more]

PMID: 29292251

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Project description: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.

Dataset Information

[Effect of aberrant H3K27me3 modification in promoter regions on cAMP response element modulator ? expression in CD4+ T cells from patients with systemic lupus erythematosus].

Publications

[Effect of aberrant H3K27me3 modification in promoter regions on cAMP response element modulator α expression in CD4<sup>+</sup> T cells from patients with systemic lupus erythematosus].

Similar Datasets

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