Abstract
The integration of single cell transcriptome and chromatin accessibility datasets enables a deeper understanding of cell heterogeneity. We performed single nucleus ATAC (snATAC-seq) and RNA (snRNA-seq) sequencing to generate paired, cell-type-specific chromatin accessibility and transcriptional profiles of the adult human kidney. We demonstrate that snATAC-seq is comparable to snRNA-seq in the assignment of cell identity and can further refine our understanding of functional heterogeneity in the nephron. The majority of differentially accessible chromatin regions are localized to promoters and a significant proportion are closely associated with differentially expressed genes. Cell-type-specific enrichment of transcription factor binding motifs implicates the activation of NF-κB that promotes VCAM1 expression and drives transition between a subpopulation of proximal tubule epithelial cells. Our multi-omics approach improves the ability to detect unique cell states within the kidney and redefines cellular heterogeneity in the proximal tubule and thick ascending limb.
Highlights
The integration of single cell transcriptome and chromatin accessibility datasets enables a deeper understanding of cell heterogeneity
Single-cell transcriptional and chromatin accessibility profiling in the adult human kidney. snRNA-seq and snATAC-seq were performed on five healthy adult kidney samples (Fig. 1a)
We used Seurat to determine the cellular composition of our snRNA-seq samples, annotate cells based on their transcriptional profiles, and inform our snATAC-seq analysis (Fig. 1a). snRNA-seq identified all major cell types within the kidney cortex (Fig. 1b, Supplementary Fig. 1a) based on the expression of lineage-specific markers (Fig. 1c, Supplementary Fig. 1b)
Summary
The integration of single cell transcriptome and chromatin accessibility datasets enables a deeper understanding of cell heterogeneity. We performed single nucleus ATAC (snATACseq) and RNA (snRNA-seq) sequencing to generate paired, cell-type-specific chromatin accessibility and transcriptional profiles of the adult human kidney. Cell-type-specific enrichment of transcription factor binding motifs implicates the activation of NF-κB that promotes VCAM1 expression and drives transition between a subpopulation of proximal tubule epithelial cells. A small subset of cells within the proximal tubule and Bowman’s capsule express vimentin, CD24, and CD1332,3 These cells have a distinct morphology and expression profile and undergo expansion after acute kidney injury[3]. Joint profiling by scRNA-seq and snATAC-seq in the adult mouse kidney has provided a framework for understanding how chromatin accessibility regulates transcription[16]; the single-cell epigenomic landscape of the human kidney has not been described. Chromatin accessibility profiling will help to identify distant regulatory regions that influence transcription via long-range interactions
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