Open chromatin map-based screening of kidney disease-associated loci at single-cell resolution

Abstract

Understanding epi-genome at single-cell scale is important to investigate several cellular phenomena such as cell-to-cell transition, cell fate determination, and gene regulatory networks. Transcription profiles of the human kidney have been relatively well-established at single-cell scale, but an epigenetic profile of the human kidney has not been achieved single-cell resolution yet. To investigate the genetic factors underlying pathogenesis of kidney diseases, it is essential to identify the effect of single nucleotide polymorphisms (SNPs) that are associated with the diseases on gene regulation. The kidneys are composed of multiple cell types including podocytes, epithelial cells of loop of Henle, and proximal tubule cells, and thus a cell type-specific map of the functional genetic elements are required to pinpoint the target cell types and to infer the role of the SNPs in the disease development. Here, I generated an open chromatin map of 22,516 cells using single-cell ATAC-seq from 6 nephrectomies of human kidneys. In addition to providing epigenetic profiles of 14 cell types in the human kidneys, I inferred cell type-specific effect of kidney disease-associated SNPs. Total 1,538 SNP associated with several phenotypes such as chronic kidney disease, IgA glomerulonephritis, and glomerular filtration rate were investigated. Among them, 423 SNPs were located on the open chromatin regions, and their regulatory effects on the target genes were verified with human kidney expression quantitative traits loci (eQTL) data. Collectively, it might be helpful to clarify the causal SNPs and their contribution on phenotype by targeting these 423 loci from open chromatin map–based pipeline at single-cell scale.