Division of Diagnostic Innovation, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Genome Biol. 2024 Jan 29;25(1):36. doi: 10.1186/s13059-024-03173-2.
Mosaic loss of Y chromosome (LOY) is the most common chromosomal alteration in aging men. Here, we use single-cell RNA and ATAC sequencing to show that LOY is present in the kidney and increases with age and chronic kidney disease.
The likelihood of a cell having LOY varies depending on its location in the nephron. Cortical epithelial cell types have a greater proportion of LOY than medullary or glomerular cell types, which may reflect their proliferative history. Proximal tubule cells are the most abundant cell type in the cortex and are susceptible to hypoxic injury. A subset of these cells acquires a pro-inflammatory transcription and chromatin accessibility profile associated with expression of HAVCR1, VCAM1, and PROM1. These injured epithelial cells have the greatest proportion of LOY and their presence predicts future kidney function decline. Moreover, proximal tubule cells with LOY are more likely to harbor additional large chromosomal gains and express pro-survival pathways. Spatial transcriptomics localizes injured proximal tubule cells to a pro-fibrotic microenvironment where they adopt a secretory phenotype and likely communicate with infiltrating immune cells.
We hypothesize that LOY is an indicator of increased DNA damage and potential marker of cellular senescence that can be applied to single-cell datasets in other tissues.
Y 染色体镶嵌缺失（LOY）是老年男性中最常见的染色体改变。在这里，我们使用单细胞 RNA 和 ATAC 测序来表明，LOY 存在于肾脏中，并随着年龄的增长和慢性肾脏病而增加。
细胞具有 LOY 的可能性取决于其在肾单位中的位置。皮质上皮细胞类型比髓质或肾小球细胞类型具有更大比例的 LOY，这可能反映了它们的增殖历史。近端肾小管细胞是皮质中最丰富的细胞类型，易受缺氧损伤。这些细胞的一部分获得与 HAVCR1、VCAM1 和 PROM1 表达相关的促炎转录和染色质可及性特征。这些受损的上皮细胞具有最大比例的 LOY，其存在预示着未来的肾功能下降。此外，具有 LOY 的近端肾小管细胞更有可能携带额外的大染色体增益，并表达促生存途径。空间转录组学将受损的近端肾小管细胞定位到一个促纤维化的微环境中，在那里它们采用分泌表型，并可能与浸润的免疫细胞进行通信。
我们假设 LOY 是 DNA 损伤增加的指标，也是细胞衰老的潜在标志物，可以应用于其他组织的单细胞数据集。
