Abstract
Background Systemic lupus erythematosus (SLE) may be triggered by gene-environment interactions. 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 pSLE patients after induction therapy.
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 a false discovery rate of <0.05.
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 treatment-naïve pSLE patients, of which over 50% appear to be more accessible in pSLE than HC, and 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. pSLE DAR were enriched for the enhancer H3K4me3. In DAR encompassing TF binding sites, pSLE samples, but not HC, were enriched for several disease-associated SNPs previously identified in lupus genome-wide association studies. Variant calling within DAR found 3864 genes belonging to 129 different biologic processes, including cellular activation in immune response and responses to external stimuli. In contrast, over 80% of peaks unique to pSLE patients post-induction therapy are 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 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 treatment-naïve pSLE patients. These pathways were absent in analyses from the same pSLE 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 immunosuppressive medication changes this epigenetic profile, making pathways responsible for inflammation and B cell activation less accessible.
Acknowledgment This work would not have been possible without the expertise of Dr Frank Jenkins. This work was funded by the Rheumatology Research Foundation.
