Genome-wide analyses of epigenetic and transcriptional variation across human immune effector cell types

A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability.
First, I report findings from an epigenome-wide association study in 52 monozygotic twin pairs discordant for type 1 diabetes (T1D) across CD4+ T cells, CD19+ B cells and CD14+CD16− monocytes. We observe a substantial enrichment of differentially variable CpG sites in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the epigenetic changes likely emerge after birth.
Second, I present results from a genome-wide analysis of transcriptional and epigenetic variability across CD14+CD16− monocytes, CD66b+CD16+ neutrophils and CD4+CD45RA+ naïve T cells from the same 125 healthy individuals. We find increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression are found to be implicated in key immune pathways and are associated with cellular properties and environmental exposure. We also observe increased sex-specific gene expression differences in neutrophils.
Taken together, these large-scale, multi-omics data reveal insights into the cell type-specific molecular events that underpin the risk for immune diseases.