Background/Purpose: Systemic lupus erythematosus (SLE) is a complex disease likely triggered by gene-environment interactions. We have shown that most of the SLE-associated haplotypes encompass genomic regions enriched for epigenetic marks associated with enhancer function in neutrophils, and T/B cells, suggesting that genetic risk is exerted through altered gene regulation. Data remain scarce on how epigenetic variance contributes to disease risk in pediatric SLE. We aim to identify differences in epigenetically-regulated chromatin architecture in treatment-naïve pediatric lupus (pSLE) patients compared to healthy children.

Methods: We used the assay for transposase-accessible chromatin-sequencing (ATACseq) to survey open chromatin in 8 treatment-naïve pSLE patients and 5 healthy children (HC). We investigated whether regions of open chromatin unique to pSLE patients might demonstrate enrichment for specific transcriptional regulators, using standard computational approaches to identify unique peaks and a false discovery rate of < 0.05. Results: The mean age of onset was 13.75 (range 7-17) years in pSLE patients; 3 out of 8 patients were male. pSLE patients were 50% African American, 38% Caucasian, and 12% Asian, with all but 1 patient identifying Hispanic. The mean SLEDAI was 12.8 (range 6-24). Differential peak analysis identified 30139 uniquely accessible sites in pSLE patients. Further analyses of these open regions revealed that 46-60% of the peaks seen only in pSLE patients are located more than 100kb from the nearest transcription start site, implying that many transcription factors (TFs) may be acting on distal enhancers to regulate transcription. Differentially accessible regions (DARs) were enriched for enhancer marks H3K4me2, H3K4me3, and H3K27ac, and contained 42 TFs that may be accessible in pSLE patients but not HC. Variant calling within DARs found 3864 genes belonging to 129 different biologic processes, most notably cellular activation in immune response, regulation of cell proliferation, and cellular responses to external stimuli (e.g., interferon).

Conclusion: Over 50% of DARs identified in pSLE patients are located far from their nearest transcription start sites, and appear to be enriched for several enhancer histone marks, implying that TF binding sites are poised for activation. Pathways of significance analyses identified immunologic pathways important in the pro-inflammatory response. Thus, patterns of chromatin accessibility suggest important roles for chromatin regulators in treatment-naïve pSLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differences-in-chromatin-architecture-in-treatment-naive-pediatric-lupus-patients/