SINGLE-CELL-RESOLVED CHROMATIN ACCESSIBLITY MAPS OF INFLAMMATORY BOWEL DISEASE INTESTINE NOMINATE CELL TYPES AND CONTEXTS MEDIATING GENETIC DISEASE RISK

To date, genome-wide association studies (GWAS) have identified 418 independent genetic risk loci contributing to inflammatory bowel disease (IBD) and its two subtypes: ulcerative colitis (UC) and Crohn’s disease (CD) (PMID:37156999). Deciphering disease mechanisms from these data is an outstanding challenge. Like other complex diseases, the majority of IBD risk variants are noncoding. If causal, they likely alter transcription factor (TF) binding, gene regulatory control loci (e.g., promoters, enhancers) and gene expression in particular cell types and contexts (e.g., age, disease).

To identify potential cell types, contexts and molecular mechanisms mediating IBD genetic risk, we built a novel resource: multiome-seq (tandem single-nuclei (sn)RNA-seq and chromatin accessibility (snATAC)-seq) of intestinal tissue from IBD patients (Fig. 1). From the snATAC-seq data, we generated a first-time atlas of chromatin accessibility (putative regulatory elements) for diverse intestinal cell types in the context of IBD.

For cell types/contexts mediating genetic risk, we reasoned that accessible chromatin will co-localize with genetic disease risk loci. Thus, we systematically tested for significant co-localization of our chromatin accessibility maps and risk variants for 1353 GWAS traits (Fig. 2A) (PMID:29662164). Globally, genetic risk variants for autoimmune diseases are enriched in accessible chromatin of immune populations, while other traits (e.g., colorectal cancer, metabolic phenotypes) are enriched in epithelial and stromal populations. Accessible chromatin maps of CD4+ T cell populations had the most significant enrichment of IBD, UC and CD risk variants. CD8+ T cells and DCs, followed by macrophages, were also significantly enriched in IBD risk loci. These enrichments were mirrored but dramatically reduced in blood-derived CD4+ T cells, CD8+ T cells and DCs of healthy control donors, highlighting the importance of tissue and disease context in deciphering genetic risk variants. In Fig. 2B, we visualize underlying data for the risk locus containing RORA, where an accessible region, unique to CD4+ T cells from inflamed tissue, overlapped an IBD risk variant; further resolution pinpoints the putative enhancer to T follicular helper (Tfh) cells. Altered regulation of at this risk locus in Tfh could promote Tfh development by repression of RORA, a Th17 regulator. Increased circulating Tfh is associated with disease activity in UC patients (PMID:32117258).

Future work includes prediction of gene regulatory mechanisms from these data (altered TF binding (PMID:36719906), gene regulatory and cell-cell communication networks (PMID:36945549)) and making predictions and underlying data web-accessible and interactively explorable to the community.