Single cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets

Abstract

Determining the epigenetic program that generates unique cell types in the kidney is critical for understanding cell-type heterogeneity during tissue homeostasis and injury response. Here, we profile open chromatin and gene expression in developing and adult mouse kidneys at single cell resolution. We show critical reliance of gene expression on distal regulatory elements (enhancers). We reveal key cell type-specific transcription factors and major gene-regulatory circuits for kidney cells. Dynamic chromatin and expression changes during nephron progenitor differentiation demonstrates that podocyte commitment occurs early and is associated with sustained Foxl1 expression. Renal tubule cells follow a more complex differentiation, where Hfn4a is associated with proximal and Tfap2b with distal fate. Mapping single nucleotide variants associated with human kidney disease implicates critical cell types, developmental stages, genes, and regulatory mechanisms. The single cell multi-omics atlas reveals key chromatin remodeling events and gene expression dynamics associated with kidney development.

A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis

“…There are more than 250 loci showing genome-wide significant association with kidney function 3 . As of now, functional annotation of target genes has only been performed for a handful of loci, such as UMOD 39 , DAB2 40 , SHROOM3 41 , DACH1 42 , and MANBA 43 . These studies indicated the critical role of the endolysosomal system in proximal tubule cells in disease development.…”

“…We reanalyzed mouse snATAC-seq data (three healthy mouse kidneys; 16,887 nuclei) and human snATAC-seq data (two healthy human kidneys; 12,720 nuclei), as described earlier 41 , 60 .…”

Transcriptome-wide association analysis identifies DACH1 as a kidney disease risk gene that contributes to fibrosis

“…To narrow the potential disease-causing variants and causal cell types, we analyzed single-cell open chromatin information of human and mouse kidney cells generated by snATAC-Seq (19).…”

Glomerular Kidney Diseases in the Single-Cell Era

“…Ongoing innovations in the single-cell technology and analysis offer better prospects to identify important cell types and states in kidney diseases. Using pseudotime analysis of single-nucleus RNA-seq and ATAC-seq data from developing and adult mouse kidneys, Miao et al delineated the trajectory of the developmental process in mice from nephron progenitor cells to podocytes and renal tubular cells (46). Pseudotime analysis may be applied to human disease data to characterize the differentiation and transition processes from one cell state to another in the presence or absence of treatment or in longitudinal studies.…”