Associate Professor Cohen Children's Medical Center Hofstra-Northwell School of Medicine New Hyde Park, New York, United States
Background: Systemic lupus erythematosus (SLE) is possibly triggered by gene-environment interactions. We showed most SLE haplotypes encompass genomic regions enriched for epigenetic marks associated with enhancer function in immune cells, suggesting altered gene regulation underlies basic genetic mechanisms. Data remain scarce on how epigenetic variance contributes to disease risk in pediatric SLE (pSLE).
Objective: To identify differences in chromatin architecture in treatment-naïve pSLE compared to healthy children (HC) and treatment-naïve adult SLE (aSLE) patients. To determine if differentially-accessible regions (DAR) in pSLE patients are associated with known disease single nucleotide polymorphisms (SNPs).
Design/Methods: We used assays for transposase-accessible chromatin-sequencing (ATACseq) in B cells of 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 methods to analyze a public aSLE GEO set. We applied the GATK4 best practices workflow from the Broad Institute to compare our 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 DAR around peaks unique to pSLE, of which over 50% appear to be more accessible in pSLE than HC. Similar results were seen in aSLE. pSLE DAR were enriched for H3K4me3, an epigenetic signature associated with active enhancers/promoters. In DAR encompassing transcription factor binding sites (TFBS), samples from pSLE, but not aSLE, were enriched for several disease-associated SNPs previously seen in lupus genome-wide association studies. Variant calling within DAR found 3864 genes belonging to 129 biologic processes, including activation in immune response, regulation of proliferation, and responses to external stimuli. Preliminary data demonstrate that DAR from the same pSLE patients post-induction therapy are not enriched for enhancers or disease-associated SNPs. Conclusion(s): We demonstrate an epigenetically-distinct profile in pSLE B cells when compared to HC, and that disease-associated SNPs are present near TFBS that are poised for activation. Treatment with immunosuppressives appears to ablate differences in chromatin architecture in pSLE B cells. Taken together, these data may indicate that transcriptional dysregulation in pSLE B cells plays an important role in pathogenesis of SLE.
Authors/Institutions: Joyce Hui-Yuen, Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States; Frank Jenkins, Northwell Health, Manhasset, New York, United States; Kaiyu Jiang, University at Buffalo, Buffalo, New York, United States; James N. Jarvis, University at Buffalo, Buffalo, New York, United States
