Epigenetic signature of human vitamin D3 and IL-10-conditioned regulatory DCs

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Abstract

During differentiation of precursor cells into their destination cell type, cell-fate decisions are enforced by a broad array of epigenetic modifications, including DNA methylation, which is reflected by the transcriptome. Thus, regulatory dendritic cells (DCregs) acquire specific epigenetic programs and immunomodulatory functions during their differentiation from monocytes. To define the epigenetic signature of human DCregs generated in vitamin D3 (vitD3) and IL-10 compared to immune stimulatory DCs (sDCs), we measured levels of DNA methylation by whole genome bisulfite sequencing (WGBS). Distinct DNA methylation patterns were acquired by DCregs compared to sDCs. These patterns were located mainly in transcriptional regulatory regions. Associated genes were enriched in STAT3-signaling and valine catabolism in DCregs; conversely, pro-inflammatory pathways, e.g. pattern recognition receptor signaling, were enriched in sDCs. Further, DCreg differentially- methylated regions (DMRs) were enriched in binding motifs specific to the immunomodulatory transcription factor Krueppel-like factor 11 (KLF11), while activator protein-1 (AP-1) (Fos:Jun) transcription factor-binding motifs were enriched in sDC DMRs. Using publicly-available data-sets, we defined a common epigenetic signature shared between DCregs generated in vitD3 and IL-10, or dexamethasone or vitD3 alone. These insights may help pave the way for design of epigenetic-based approaches to enhance the production of DCregs as effective therapeutic agents.

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