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

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 profiled 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 define key cell type-specific transcription factors and major gene-regulatory circuits for kidney cells. Dynamic chromatin and expression changes during nephron progenitor differentiation demonstrated that podocyte commitment occurs early and is associated with sustained Foxl1 expression. Renal tubule cells followed a more complex differentiation, where Hfn4a was associated with proximal and Tfap2b with distal fate. Mapping single nucleotide variants associated with human kidney disease identified critical cell types, developmental stages, genes, and regulatory mechanisms. We provide a global single cell resolution view of chromatin accessibility of kidney development. The dataset is available via interactive public websites. Overall design: 2 P0 mouse kidney snATAC-seq samples, 3 adult mouse kidney snATAC-seq samples, 1 P0 mouse kidney scRNA-seq sample, 1 adult mouse kidney scRNA-seq sample, 2 P0 mouse kidney bulk ATAC-seq samples, 2 3-week mouse kidney bulk ATAC-seq samples, and 2 8-week mouse kidney bulk ATAC-seq samples

解析肾脏中生成独特细胞类型的表观遗传程序，对于理解组织稳态与损伤应答过程中的细胞类型异质性至关重要。本研究对发育阶段及成年小鼠肾脏的开放染色质与基因表达开展了单细胞分辨率全景分析。我们证实基因表达高度依赖远端调控元件（enhancers，即增强子）。我们明确了肾脏细胞关键的细胞类型特异性转录因子及主要基因调控环路。肾单位祖细胞分化过程中的染色质与表达动态变化研究显示，足细胞定型发生较早，且与Foxl1基因的持续表达密切相关。肾小管细胞的分化过程更为复杂，其中Hfn4a与近端肾小管命运相关，而Tfap2b则与远端肾小管命运相关。通过定位与人类肾脏疾病相关的单核苷酸变异，本研究明确了关键细胞类型、发育阶段、相关基因及调控机制。我们提供了肾脏发育过程中染色质可及性的全局单细胞分辨率图谱。该数据集可通过交互式公共网站获取。实验整体设计：2份出生后0天（P0）小鼠肾脏单核ATAC测序（snATAC-seq）样本、3份成年小鼠肾脏单核ATAC-seq样本、1份出生后0天（P0）小鼠肾脏单细胞RNA测序（scRNA-seq）样本、1份成年小鼠肾脏scRNA-seq样本、2份出生后0天（P0）小鼠肾脏批量ATAC测序（bulk ATAC-seq）样本、2份3周龄小鼠肾脏bulk ATAC-seq样本以及2份8周龄小鼠肾脏bulk ATAC-seq样本。