Background/Purpose: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that involves multiple organ systems and periods of variable disease activity. Although SLE, especially in patients with high disease activity, is often associated with increased circulating pro-inflammatory cytokines, a clear understanding of immune dysfunction preceding and during high disease activity is lacking. The identification of genes and gene pathways that are differentially regulated between SLE and healthy individuals, as well as between patients with varying disease activity, may allow better selection of directed therapeutics and development of new targets. To address this knowledge gap, we determined the chromatin accessibility landscape of three distinct compartments of the lupus immune system using the ‘Assay for Transposase Accessible Chromatin Sequencing’ (ATAC-seq) method.

Methods: Monocytes, B cells, and T cells were sorted by flow cytometry from frozen PBMCs of 9 SLE patients and 5 matched controls. Sorted cell fractions were processed for high-throughput open chromatin profiling by ATAC-seq. Reads were aligned to the hg19 genome and regions of enriched chromatin accessibility “peaks” were identified with MACS2. For each cell type, we identified the consensus set of epigenetically active peaks across all 14 subjects. We conducted enrichment tests of identified loci using the GREAT tool and performed differential accessibility analysis using the edgeR package in R. Transcription factor binding motif enrichment and overlaps with known SLE risk haplotypes were also determined.

Results: All cell types showed similar percentages (39~43%) of coding transcripts with open chromatin in promoters. The peaks unique to each profile were enriched in genomic loci specific to their cellular function: T cell development/activation for T cells, B cell development/activation for B cells, and phagocytosis, apoptotic cell clearance, and inflammatory cytokine regulation for monocytes. Analysis of transcription factor binding motifs in ATAC peaks identified cell type specific promoters including myeloid and lymphoid cell lineage commitment transcription factors. Quantitative analysis revealed chromatin accessibility loci that discriminate between SLE and controls, as well as between high and low disease activity. Of the total 53338 monocyte specific peaks observed in at least 7 samples, 308 peaks allowed us to differentiate between SLE and controls, whereas in T and B cells the numbers were 57 of 34818 and 553 of 39425, respectively. Motif analysis revealed that many consensus peaks occupy binding sites of cohesin complex subunits, suggesting that long-range chromatin interactions may mediate immune responses that drive SLE progression. In addition, of 2519 SLE genetic risk SNPs, 320 were located within an open chromatin peak suggesting functional relevance.

Conclusion: Our data suggest that SLE and controls show cell type specific differences in their chromatin accessibility, and these profiles differ across the spectrum of disease activity. Chromatin profiling, integrated with transcriptome data, may expand our knowledge of how specific cell states drive SLE pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cell-type-specific-epigenetic-features-of-systemic-lupus-erythematosus/