Abstract
Purpose :
Previous genome-wide association studies (GWAS) show that a substantial proportion of genetic risk for autoimmune disease falls within accessible regions of the cell types associated with the disease. Chromatin accessibility provides critical information about DNA cis- and trans-regulatory elements. Despite its importance, much remains to be learned about the noncoding genome and epigenetic regulation in autoimmune eye diseases and pathogenic immune cells. Therefore, we map an epigenetic landscape of chromatin accessibility in peripheral blood from healthy individuals and patients with Vogt-Koyanagi-Harada (VKH) and Behcet’s disease.
Methods :
This study involved healthy individuals (N=12), patients with VKH disease (N=12), and Behcet’s disease (N=13) at Zhongshan Ophthalmic Center, China. Peripheral blood mononuclear cells (PBMCs) were collected and processed using a single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq). The data were aligned to the GRh38 reference genome and quantified by the Cell Ranger pipeline. We employed UMAP, a nonlinear dimensionality reduction method to visualize the data, and MACS2 to perform peak calling. We identified each cell type-specific transcription factor (TF) activity using ChromVAR.
Results :
We generated high-dimensional scATAC-seq data in PBMCs and identified diverse epigenetic regulatory landscapes. A detailed analysis of the landscape of healthy individuals showed distinct transcription factor activities in double-negative B cells and unraveled the regulatory trajectory of B cell development. A significant decrease in the frequency of Th2 cells in Behcet’s disease patients was noticed compared to healthy individuals (p=0.0146). Integration of scATAC-seq data with autoimmune disease GWAS datasets revealed target cell types as well as pathogenic TFs for VKH and Behcet’s disease, such as those related to NF-κB and STAT family.
Conclusions :
The application of scATAC-seq enables unbiased identification of cell type-specific active DNA regulatory elements. This study characterizes epigenomic profiles of peripheral immunity and unveils the regulatory programs of VKH and Behcet’s disease. These data represent a valuable resource for testing diagnostic and therapeutic strategies against autoimmune eye diseases.
This is a 2021 ARVO Annual Meeting abstract.