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Abstract
Background IKZF1 (Ikaros), IKZF2 (Helios) and IKZF3 (Aiolos) are candidate genes for Systemic Lupus Erythematosus (Pmeta<5x10–8). The proteins are members of the Kruppel zinc finger family of transcription factors (TF). These three TFs are important regulators of haematopoesis and lymphocyte function, making good functional candidates for lupus. Helios-deficient mice acquire an auto-inflammatory phenotype in later life, resulting in increased numbers of activated CD4+ and CD8+ T-cells and germinal centre B-cells, culminating in autoantibody production. Murine knockouts of Ikzf1 and Ikzf3 also exhibit problems with immune function. The underlying mechanism(s) for the genetic associations are currently unknown.
Methods We used ChIP-Seq to determine the DNA binding sites of Ikaros, Helios and Aiolos in the GM12878 EBV-lymphoblastoid cell line and for Helios in Jurkat T-cells by implementing the uniform processing pipeline for TF ChIP-Seq (ENCODE Phase 3). We compared the unique binding sites of each Ikaros transcription factor using MAnorm2 and identified biological pathways enriched for target-genes using EnrichR.
Results 21,334 high-confidence peaks were called for Aiolos, 9,027 for Ikaros, 13,583 for Helios in B-cells and 5,070 peaks for Helios in T-cells. Ikaros and Aiolos target-genes share a similar pattern of enrichment within immune-related pathways. There was a distinct tissue-specific pattern of enrichment for Helios binding sites in T-cells compared with B-cells within immune-related pathways for: Chemokine signalling- CCL27 (C-C Motif Chemokine Ligand 27); Regulation of Toll-like receptor signalling- SQTM1 (Sequestosome 1), SIGIRR (single immunoglobulin IL-1R-related receptor; IL1 signalling- SQTM1, TRAF6 (TNF Receptor-Associated Factor 6); IL17 signalling- IL17RE (Interleukin 17 Receptor E), TRAF3IP2 (TRAF3 Interacting Protein 2) and TRAF6.
Conclusions Our study describes the first comprehensive analysis of Ikaros transcription factors in SLE using ChIP-Seq. The cell-type specific differences of Helios target-genes in B-cells compared with T-cells suggest separate immune-functions in these two cell-types.
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