Muto Yoshiharu, Dixon Eryn E, Yoshimura Yasuhiro, Wu Haojia, Omachi Kohei, Ledru Nicolas, Wilson Parker C, King Andrew J, Eric Olson N, Gunawan Marvin G, Kuo Jay J, Cox Jennifer H, Miner Jeffrey H, Seliger Stephen L, Woodward Owen M, Welling Paul A, Watnick Terry J, Humphreys Benjamin D
Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.
Nat Commun. 2022 Oct 30;13(1):6497. doi: 10.1038/s41467-022-34255-z.
Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal disease characterized by progressive expansion of kidney cysts. To better understand the cell types and states driving ADPKD progression, we analyze eight ADPKD and five healthy human kidney samples, generating single cell multiomic atlas consisting of ~100,000 single nucleus transcriptomes and ~50,000 single nucleus epigenomes. Activation of proinflammatory, profibrotic signaling pathways are driven by proximal tubular cells with a failed repair transcriptomic signature, proinflammatory fibroblasts and collecting duct cells. We identify GPRC5A as a marker for cyst-lining collecting duct cells that exhibits increased transcription factor binding motif availability for NF-κB, TEAD, CREB and retinoic acid receptors. We identify and validate a distal enhancer regulating GPRC5A expression containing these motifs. This single cell multiomic analysis of human ADPKD reveals previously unrecognized cellular heterogeneity and provides a foundation to develop better diagnostic and therapeutic approaches.
常染色体显性多囊肾病（ADPKD）是终末期肾病的主要遗传病因，其特征是肾囊肿进行性增大。为了更好地了解驱动ADPKD进展的细胞类型和状态，我们分析了8个ADPKD患者和5个健康人的肾脏样本，生成了一个单细胞多组学图谱，其中包含约100,000个单核转录组和约50,000个单核表观基因组。促炎、促纤维化信号通路的激活由具有修复转录组特征失败的近端肾小管细胞、促炎成纤维细胞和集合管细胞驱动。我们将GPRC5A鉴定为囊肿内衬集合管细胞的标志物，该标志物显示NF-κB、TEAD、CREB和视黄酸受体的转录因子结合基序可用性增加。我们鉴定并验证了一个调控GPRC5A表达的远端增强子，该增强子包含这些基序。这项对人类ADPKD的单细胞多组学分析揭示了以前未被认识的细胞异质性，并为开发更好的诊断和治疗方法奠定了基础。
