CD4+ T cells from children with active juvenile idiopathic arthritis show altered chromatin features associated with transcriptional abnormalities

Abstract

Juvenile idiopathic arthritis (JIA) is one of the most common chronic diseases in children. While clinical outcomes for patients with juvenile JIA have improved, the underlying biology of the disease and mechanisms underlying therapeutic response/non-response are poorly understood. We have shown that active JIA is associated with distinct transcriptional abnormalities, and that the attainment of remission is associated with reorganization of transcriptional networks. In this study, we used a multi-omics approach to identify mechanisms driving the transcriptional abnormalities in peripheral blood CD4+ T cells of children with active JIA. We demonstrate that active JIA is associated with alterations in CD4+ T cell chromatin, as assessed by ATACseq studies. However, 3D chromatin architecture, assessed by HiChIP and simultaneous mapping of CTCF anchors of chromatin loops, reveals that normal 3D chromatin architecture is largely preserved. Overlapping CTCF binding, ATACseq, and RNAseq data with known JIA genetic risk loci demonstrated the presence of genetic influences on the observed transcriptional abnormalities and identified candidate target genes. These studies demonstrate the utility of multi-omics approaches for unraveling important questions regarding the pathobiology of autoimmune diseases.

Identification of Mechanisms by Which Genetic Susceptibility Loci Influence Systemic Sclerosis Risk Using Functional Genomics in Primary T Cells and Monocytes

“…Our results revealed that 3‐dimensional chromatin structure is largely preserved between SSc patients and healthy controls, at least in CD4+ T cells and CD14+ monocytes derived from peripheral blood. So far, there is only 1 published study that attempted to observe differences at the interaction level between patients and healthy controls in CD4+ T cells from juvenile idiopathic arthritis patients ( 59 ). However, no differences at the interactome level were observed, which supports our hypothesis and emphasizes the difficulty to describe these subtle differences with current technology.…”

Comparison of the three-dimensional chromatin structures of adolescent and adult peripheral blood B cells: implications for the study of pediatric autoimmune diseases

“…Whether these data sets can be used to interrogate genetic mechanisms in childhood onset diseases like JIA is unknown. Until now, the standard has been for investigators of these diseases to generate their own reference data from healthy children (8, 33, 34), something that is difficult and costly to do. The field of pediatric autoimmunity would benefit greatly if it could be ascertained that existing reference data sets are applicable, especially at autoimmune risk loci.…”

Functional genomics in primary T cells and monocytes identifies mechanisms by which genetic susceptibility loci influence systemic sclerosis risk

“…Our results reveal that 3D chromatin structure is largely preserved between SSc patients and healthy controls at least in CD4 + T cells and CD14 + monocytes, which make them difficult to interpret. So far, there is only one published study in which authors attempt to observe differences at the interaction level between patients and healthy controls in CD4 + T cells from juvenile idiopathic arthritis patients (48). However, no differences at the interactomic level were observed, which supports our hypothesis and underlines the difficulty to describe these subtle differences with current technology.…”