Concordant B and T Cell Heterogeneity Inferred from the multi-omic Landscape of Peripheral Blood Mononuclear Cells in a Crohn’s Disease Cohort

Abstract

Abstract Background and Aims Crohn’s disease is characterised by inflammation in the gastrointestinal tract due to a combination of genetic, immune, and environmental factors. Transcriptomic and epigenomic profiling of intestinal tissue of Crohn’s disease patients have revealed valuable insights into pathology, but have not been conducted jointly on less invasive peripheral blood mononuclear cells [PBMCs]. Furthermore, the heterogeneous responses to treatments among individuals with Crohn’s disease imply hidden diversity of pathological mechanisms. Methods We employed single nucleus multi-omic analysis, integrating both snRNA-seq and snATAC-seq of PBMCs with a variety of open source, bioinformatics applications. Results Our findings reveal a diverse range of transcriptional signatures among individuals, highlighting the heterogeneity in PBMC profiles. Nevertheless, striking concordance between three heterogeneous groups was observed across B cells and T cells. Differential gene regulatory mechanisms partially explain these profiles, notably including a signature involving TGFß signalling in two individuals with Crohn’s disease. A mutation mapped to a transcription factor binding site within a differentially accessible peak associated with the expression of this pathway, with implications for a personalised approach to understanding disease pathology. Conclusions This study highlights how multi-omic analysis can reveal common regulatory mechanisms that underlie heterogeneity of PBMC profiles, one of which may be specific to inflammatory disease.