Chromatin accessibility changes underlying progression from islet autoantibody positivity to type 1 diabetes

Type 1 diabetes (T1D) usually has a preclinical phase identified by the presence of circulating autoantibodies to pancreatic islet antigens, and most young children who have multiple autoantibodies progress to diabetes within 10 years. While autoantibodies denote underlying islet autoimmunity, how this process is initiated and then progresses to clinical diabetes on a background of genetic susceptibility is not clearly understood. Only one study has thus far reported changes in gene expression in isolated immune cells associated with progression to islet autoimmunity. We analysed chromatin accessibility by ATAC-seq in CD4+ T cells in four genetically at-risk children with islet autoantibodies who progressed to diabetes in ≤ 3 years (‘progressors’), compared to five at-risk children matched for sex, age and HLA who had not progressed (‘non-progressors). From ATAC-seq data, we generated the first map of chromatin accessibility in T cells of islet autoantibody-positive children. Progression was associated with a subtle reconfiguration of regulatory chromatin regions, and some of the chromatin conformation changes could be linked to progression associated expression changes at cytotoxic genes. ATAC-seq analysis was performed on CD4+ T cells sorted from PBMC samples of 9 genetically at-risk children with autoantibodies to two or more islet antigens, four of whom progressed to T1D. Autoantibodies measured were as follows: insulin autoantibodies (IAA), glutamic acid decarboxylase 65 autoantibodies (GADA), tyrosine phosphatase-like insulinoma antigen autoantibodies (IA2A) and transporter 8 (COOH R/W dimer) (ZnT8A) autoantibodies. Positive cut-offs for these antibodies were defined as IAA ≥ 0.7 mU/L, GADA > 5.0 U/mL, IA2A > 3.0 U/mL and ZnT8A ≥ 3.1U/mL, respectively. Note: This deposition provides read counts for each peak in each sample, from which our analyses can be reproduced, but the raw sequence data files cannot be made publicly available because of privacy issues with human samples. The raw sequence data will be made available for appropriate research projects upon application to the WEHI Data Access Committee ([e-mail]).