Aberrant H3K4me3 modification of immune response genes in CD4+ T cells of patients with systemic lupus erythematosus

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: ChIP-seq; H3K4me3; Immune response genes; Systemic lupus erythematosus.