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

Zhen Miao,Michael S Balzer,Rojesh Shrestha,Amy Kwan,Junnan Wu,Katalin Susztak,Marco Pontoglio,Klaus H Kaestner,Hongbo Liu,Ziyuan Ma,Junhyong Kim,Mingyao Li,Tamas Aranyi,Ayano Kondo

doi:10.1038/s41467-021-22266-1

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.

Highlights

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
We found that the single nuclei open chromatin set showed good concordance with bulk ATAC-seq samples, with most of the peaks in bulk ATAC-seq data captured by the single nuclei data
We identified key cell type-specific regulatory networks for kidney cells, defined the cellular differentiation trajectory, characterized regulatory dynamics and identified key driving transcription factors (TFs) for nephron development, especially for the terminal differentiation of epithelial cells

Summary

Introduction

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. We profile open chromatin and gene expression in developing and adult mouse kidneys at single cell resolution. The single cell multi-omics atlas reveals key chromatin remodeling events and gene expression dynamics associated with kidney development. The renal vesicle undergoes segmentation and elongation, giving rise to epithelia from the podocytes to the distal convoluted tubules, while the ureteric bud becomes the collecting duct. While single cell RNA sequencing (scRNA-seq) has improved our understanding of kidney development in mice and humans[9,10,13,14], it provides limited information of TFs, which are usually expressed at low levels. We generate a single cell open chromatin and corresponding expression survey for the developing and adult mouse kidney, which is available to the community via searchable websites

Methods

Results

Conclusion