Functional relevance of genetic variants in autoimmune disease

Autoimmune diseases are underpinned by immune cell dysfunction that can be impacted by inherited genetic variation. We recently used single-cell transcriptomics and epigenomics to map cell type-specific chromatin accessibility and gene expression at autoimmune genetic variant loci and found that many loci had specific regulatory potential in cells associated with the germinal centre (GC), a dynamic immunological structure where autoreactive B cells are regulated to prevent autoimmunity. We are now interrogating whether these autoimmune genetic variants are involved in regulating gene expression in GC cells with functional genomic assays on ex vivo culture systems and single-cell based screens.

Disease-specific gene regulatory networks in autoimmunity

Building on findings in healthy patient datasets, and concurrent with detailed mechanistic studies, we want to understand whether the B cell response in patients with autoimmune disease is associated with disease-specific epigenetic dysregulation or regulatory element function. This question has been examined previously in peripheral blood-derived B cells populations, but whether such disease-specific epigenomic patterns exist in the GC response of patients with autoimmune disease has not been determined. This is especially important as the GC is a major site of immune cell fate decisions.

Immune-specific chromatin pathways

Our current understanding of chromatin-based gene regulation in immune cells relies upon the function of ubiquitously-expressed epigenetic readers and writers. However, specific chromatin readers and writers are uniquely over-expressed or restricted to immune cell lineages. This project aims to identify such chromatin-associated factors and investigate how and where they interact with the epigenomes of different immune cell lineages. We leverage both in vitro and ex vivo immune cell culture methods, combined with cutting edge bulk and single-cell genomics to understand how normal, and disease-specific, gene regulatory networks are defined and controlled by chromatin readers and writers.