There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidney’s active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks.

需要定义控制人类肾细胞健康、损伤和修复状态的基因激活或抑制区域，以了解肾脏疾病的分子发病机制并设计治疗策略。基因表达与定义调控元件的表观遗传特征的全面整合仍然是一个重大挑战。我们测量双单核 RNA 表达和染色质可及性、DNA 甲基化以及 H3K27ac、H3K4me1、H3K4me3 和 H3K27me3 组蛋白修饰，以破译参考和适应性损伤状态下肾脏的染色质景观和基因调控。我们建立了一个空间锚定的表观基因组图谱来定义肾脏在整个基因组中的活跃、沉默和可调节的染色质区域。使用该图谱，我们注意到不同上皮细胞类型对适应性损伤的不同控制。 ELF3 、 KLF6和KLF10的近端小管细胞转录因子网络调节健康与损伤之间的转变，而在粗升肢细胞中，这种转变由NR2F1调节。此外， ELF3 、 KLF6和KLF10的组合扰动区分了两种适应性近端肾小管细胞亚型，其中一种在敲除后表现出修复轨迹。该图谱将作为通过重新编程基因调控网络促进靶向细胞特异性治疗的基础。