Spatial & Functional
Genomics Affinity Group

Autoimmune and inflammatory disease

The susceptibility to autoimmune diseases such as rheumatoid arthritis (RA), type 1 diabetes (T1D), multiple sclerosis (MS), celiac disease (CD), myasthenia gravis (MG), systemic lupus erythematosus (SLE) and the auto-inflammatory diseases psoriasis and inflammatory bowel disease (Crohns disease and ulcerative colitis) have strong but complex genetic components. We are applying our 3D genomics approaches to multiple, disease-relevant immune cell populations including monocytes, naïve B and T lymphocytes, regulatory T cells, follicular helper T cells, germinal center B cells, memory Th1, Th2, Th17, and CTL cells. Recently we have completed a high-resolution open chromatin and 3-dimensional promoter interactomes in human follicular helper (TFH) T cells, a disease-relevant cell type required for the production of autoantibodies and use these maps to gain insight into the genetic basis of systemic lupus erythematosus (SLE). We identified ~350 putative functional SLE variants based on their accessibility in TFH open chromatin. Open promoter variants were enriched at genes highly expressed in TFH, and non-promoter open variants were enriched for enhancer signatures. Importantly, we find that 50% of non-promoter variants 'skip' the nearest promoter to physically interact only with distant genes. Gene ontology confirmed that genes physically interacting with SLE variants in 3 dimensions reside in highly TFH- and SLE-relevant networks, while the set of genes residing nearest to these variants in 1 dimension do not. An example of this is an accessible intronic SLE variant at the LPP locus that loops over 1 Mb to interact with the promoter of the master TFH transcription factor gene BCL6. CRISPR/CAS9 genome editing confirmed that this variant resides in a novel distal enhancer required for normal expression of BCL6. This 3-dimensional variant-to-gene mapping approach gives crucial insight into the disease-associated regulatory architecture of the human genome.