Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Department of Rheumatology, Xiangya Hospital of Central South University, Changsha, Hunan, China.
Int Immunopharmacol. 2024 Mar 30;130:111748. doi: 10.1016/j.intimp.2024.111748. Epub 2024 Mar 2.
Increasing evidence has highlighted the significant role of histone modifications in pathogenesis of systemic lupus erythematosus (SLE). However, few studies have comprehensively analyzed trimethylation of histone H3 lysine 4 (H3K4me3) features at specific immune gene loci in SLE patients.
We conducted H3K4me3 chromatin immunoprecipitation sequencing (ChIP-seq) on CD4 T cells from SLE patients and healthy controls (HC). Differential H3K4me3 peaks were identified, followed by enrichment analysis. We integrated online RNA-seq and DNA methylation datasets to explore the relationship between H3K4me3 modification, DNA methylation and gene expression. We validated several upregulated peak regions by ChIP-qPCR and confirmed their impact on gene expression using RT-qPCR. Finally, we investigated the impact of H3K4 methyltransferases KMT2A on the expression of immune response genes.
we identified 147 downregulated and 2701 upregulated H3K4me3 peaks in CD4 T cells of SLE. The upregulated peaks primarily classified as gained peaks and enriched in immune response genes such as FCGR2A, C5AR1, SERPING1 and OASL. Genes with upregulated H3K4me3 and downregulated DNA methylations in the promoter were highly expressed in SLE patients. These genes, including OAS1, IFI27 and IFI44L, were enriched in immune response pathways. The IFI44L locus also showed increased H3K27ac modification, chromatin accessibility and chromatin interactions in SLE. Moreover, knockdown of KMT2A can downregulate the expression of immune response genes in T cells.
Our study uncovers dysregulated H3K4me3 modification patterns in immune response genes loci, which also exhibit downregulated DNA methylation and higher mRNA expression in CD4 T cells of SLE patients.
越来越多的证据强调了组蛋白修饰在系统性红斑狼疮（SLE）发病机制中的重要作用。然而，很少有研究全面分析 SLE 患者特定免疫基因座处组蛋白 H3 赖氨酸 4（H3K4me3）的三甲基化特征。
我们对 SLE 患者和健康对照（HC）的 CD4 T 细胞进行了 H3K4me3 染色质免疫沉淀测序（ChIP-seq）。鉴定了差异 H3K4me3 峰，然后进行了富集分析。我们整合了在线 RNA-seq 和 DNA 甲基化数据集，以探讨 H3K4me3 修饰、DNA 甲基化和基因表达之间的关系。我们通过 ChIP-qPCR 验证了几个上调的峰区，并使用 RT-qPCR 证实了它们对基因表达的影响。最后，我们研究了 H3K4 甲基转移酶 KMT2A 对免疫反应基因表达的影响。
我们在 SLE 的 CD4 T 细胞中鉴定出 147 个下调和 2701 个上调的 H3K4me3 峰。上调的峰主要分类为获得峰，富集于免疫反应基因，如 FCGR2A、C5AR1、SERPING1 和 OASL。在 SLE 患者中，H3K4me3 上调且启动子区 DNA 甲基化下调的基因表达水平较高。这些基因，包括 OAS1、IFI27 和 IFI44L，富集于免疫反应途径。IFI44L 基因座也显示出在 SLE 中 H3K27ac 修饰、染色质可及性和染色质相互作用增加。此外，在 T 细胞中敲低 KMT2A 可以下调免疫反应基因的表达。
我们的研究揭示了免疫反应基因座处 H3K4me3 修饰模式的失调，SLE 患者的 CD4 T 细胞中还表现出 DNA 甲基化下调和 mRNA 表达升高。
