Date: Monday, November 9, 2020
Session Type: Poster Session D
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic lupus erythematosus (SLE) is possibly triggered by gene-environment interactions. We showed most of the SLE haplotypes encompass genomic regions enriched for epigenetic marks associated with enhancer function in immune cells, suggesting altered gene regulation. Data remain scarce on how epigenetic variance contributes to disease risk in pediatric SLE (pSLE). Our objectives were to identify differences in chromatin architecture in treatment-naïve pSLE compared to healthy children (HC) and to compare these differences to epigenetic data from treatment-naïve adult SLE patients.
Methods: We used the assay for transposase-accessible chromatin-sequencing (ATACseq) in 8 treatment-naïve pSLE patients and 5 HC to investigate whether regions of open chromatin unique to pSLE patients demonstrate enrichment for transcriptional regulators, using standard computational approaches and a false discovery rate of < 0.05. We used similar methodology to interrogate adult SLE data from a public GEO set to compare our pSLE findings.
Results: The mean age of onset was 13.75 (range 7-17) years in pSLE, and mean SLEDAI was 12.8 (range 6-24). We identified 245 differentially accessible regions (DAR) around peaks unique to pSLE, of which over 50% appear to be more accessible in pSLE than HC. Of the unique peaks, 46-60% are located more than 100kb from the nearest transcription start site (nTSS), implying many transcription factors may be acting on distal enhancers to regulate transcription. Variant calling within DAR found 3864 genes belonging to 129 different biologic processes (BP), most notably cellular activation in immune response, regulation of proliferation, and responses to external stimuli. Similar results were seen in adult SLE data: over 50% of peaks in adult SLE are located distal to nTSS, and 3263 genes within DAR belong to 135 different BP, including cellular activation in immune response and complement activation.
Conclusion: We demonstrate an epigenetically-distinct profile in pSLE B cells when compared to HC, indicating pSLE B cells are predisposed for disease development. Pathways of significance analyses identified immunologic pathways important in the pro-inflammatory response in pSLE and adult SLE patients. Thus, increased chromatin accessibility in genomic regions controlling activation of the inflammatory and immune responses suggest transcriptional dysregulation of key players in immune cell activation plays an important role in pathogenesis of SLE.
To cite this abstract in AMA style:Hui-Yuen J, Jenkins F, Jiang K, Malkiel S, Diamond B, Jarvis J. Differences in Chromatin Architecture Between Treatment Naïve Pediatric and Adult Lupus Patients [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/differences-in-chromatin-architecture-between-treatment-naive-pediatric-and-adult-lupus-patients-2/. Accessed May 13, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differences-in-chromatin-architecture-between-treatment-naive-pediatric-and-adult-lupus-patients-2/