Single nucleus chromatin profiling of human kidneys reveals key cell types and a regulator of diabetic kidney disease

Abstract

We performed a comparative analysis of 6 normal and 4 DKD human kidneys through examining single-nucleus chromatin accessibility by single-nucleus ATAC-seq (snATAC-seq). We mapped the cell type-specific and DKD-specific open chromatin landscape and found that genetic variants associated with kidney diseases were significantly enriched in the proximal tubule- (PT) and injured PT-specific open chromatin regions in DKD samples. BACH1 was identified as a core transcription factor of injured PT cells, and its binding target genes were highly associated with fibrosis and inflammation that were also key features of injured PT cells. Moreover, we identified direct target genes of BACH1, and indicated that BACH1 binding regions showed increased chromatin contact frequency with promoters of their target genes in DKD. By generating BACH1-enhancer knockout cell line, we showed the direct regulation of ATP9A, one of the newly identified BACH1 target genes, is directly regulated by BACH1.