Overall Downregulation of mRNAs and Enrichment of H3K4me3 Change Near Genome-Wide Association Study Signals in Systemic Lupus Erythematosus: Cell-Specific Effects.

Zhe Zhang,Michele A Petri,Lihua Shi,Kathleen E Sullivan,Li Song,Kelly Maurer

doi:10.3389/fimmu.2018.00497

Abstract

This study was designed to define gene expression and H3K4me3 histone modifications in T cells, B cells, and monocytes in systemic lupus erythematosus (SLE). Array studies of total peripheral blood mononuclear cells have demonstrated gene expression signatures related to neutrophils, interferon, and other inflammatory pathways. It is not clear how consistent these effects are across different cell types. In this study, RNA-seq and chromatin immunoprecipitation-seq were utilized to identify gene expression patterns and H3K4me3 histone modifications related to promoter activation in SLE. Across the three cell types, there was 55% concordance for gene expression changes related to SLE. Key conserved pathways were ribosome biogenesis among upregulated genes and heat shock response among downregulated genes. ETS family transcription factors (TFs) and STAT1 were revealed as common regulators by position weight matrices. When epigenetic changes were leveraged with gene expression, the pivotal TFs ATF3 and FOS were defined with ATF3 also cross-referencing with gene expression-identified TFs. Genome-wide association study (GWAS) single nucleotide polymorphisms associated with SLE were cross-referenced with both mRNA and H3K4me3 changes in SLE. Baseline mRNA expression and H3K4me3 peak height was higher at sites that cross-referenced with GWAS signals, however, all three cell types exhibited an overall decrease in expression of GWAS-associated RNAs differentially expressed in SLE. H3K4me3 changes in SLE were also enriched in GWAS-associated sites. In summary, the SLE disease process is associated with both shared and cell-specific changes in gene expression and epigenetics. Surprisingly, GWAS-associated RNAs were overall markedly decreased across all three cell types. TF analysis identified ATF3, FOS, STAT1, and ETS family members as critical, all pathways with a recognized relationship to the SLE disease process. GWAS signals clearly mark both cell-type specific changes in SLE as well as concordant changes across all three cell types. Interpretation of single nucleotide polymorphism effects in SLE will require tissue-specific mechanistic studies and therapeutics will require mechanistic studies in multiple cell types.

Highlights

Systemic lupus erythematosus (SLE) is the quintessential systemic autoimmune disease
To understand whether conserved pathways affect multiple cell types in systemic lupus erythematosus (SLE), we performed a detailed analysis of RNA and H3K4me3 changes in SLE
We selected patients with low-disease activity to focus on core facets of the SLE transcriptome and to avoid medication effects. 55% of the genes with altered expression were concordant across the three cell types

Summary

Introduction

Systemic lupus erythematosus (SLE) is the quintessential systemic autoimmune disease. In spite of enormous effort to identify a common pathway that links all clinical and laboratory features, only the interferon signature has been identified consistently across multiple laboratories [2,3,4] This major advance in the understanding of SLE arose from the study of peripheral blood mononuclear cells (PBMC) by gene expression arrays and is associated with a broad range of autoimmune diseases [5,6,7]. We hypothesized that different cell types in peripheral blood are impacted by the SLE disease process in both coordinate and distinct manners and key commonalities could be dissected by using a joint transcriptomic and epigenetic approach in purified cell types. Recognition of distinct cell effects is critical for interpretation of genome-wide association studies (GWASs) where efforts to examine mechanism may require a tissue-specific approach

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