14 - Differences in Chromatin Accessibility Pre- and Post-Induction Therapy in Pediatric Lupus

Poster Number: 14
Publication Number: 14.110

Joyce Hui-Yuen, Cohen Children's Medical Center, New Hyde Park, NY, United States; Kaiyu Jiang, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Buffalo, NY, United States; Susan Malkiel, Feinstein Institutes for Medical Research, Manhasset, NY, United States; Betty Diamond, The Feinstein Institutes for Medical Research, Manhasset, NY, United States; James N. Jarvis, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Buffalo, NY, United States

Background: Systemic lupus erythematosus (SLE) may be triggered by gene-environment interactions. Data are scarce on how epigenetic variance contributes to pediatric SLE (pSLE) disease risk.

Objective: To identify differences in chromatin accessibility in treatment-naïve pSLE compared to healthy children (HC) and pSLE patients post-induction therapy.

Design/Methods: We used assays for transposase-accessible chromatin-sequencing (ATACseq) in 8 pSLE patients pre- and post-induction therapy and 5 HC to investigate whether regions of open chromatin unique to pSLE patients demonstrate enrichment for transcriptional regulators, using standard computational approaches and false discovery rate of < 0.05.

Results: The mean age of onset was 13.75 (range 7-17) years in pSLE, and mean lupus activity index was 12.8 (range 6-24). There were 245 differentially accessible regions (DAR) around peaks unique to treatment-naïve pSLE patients, of which 64.3% were more accessible in pSLE than HC. Many of the DAR are located more than 100kb from the nearest transcription start site (nTSS), implying transcription factors (TF) may be acting on distal enhancers to regulate transcription. In DAR encompassing TF binding sites, pSLE samples, but not HC, were enriched for disease-associated SNPs previously identified in lupus association studies. Variant calling within DAR found 3864 genes belonging to disease-relevant biologic processes such as cellular activation in immune response. In contrast, 86.7% of peaks unique to pSLE patients post-induction therapy were located distal to nTSS. Induction therapy for pSLE patients included corticosteroids in all patients, cyclophosphamide in 5, and mycophenolate in 3. DAR from the pSLE patients post-induction therapy were not enriched for enhancers or disease-associated SNPs.Conclusion(s): 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 pro-inflammatory response in treatment-naïve pSLE patients, that were absent in analyses from the same patients post-induction therapy. Thus, increased chromatin accessibility in genomic regions controlling activation of inflammatory and immune responses suggest transcriptional dysregulation of key players in immune cell activation plays an important role in pathogenesis of SLE. Treatment with corticosteroids and immunosuppressives changes this epigenetic profile, making pathways responsible for inflammation and B cell activation less accessible.