PDF(Pubmed)
Abstract：
Kidney formation and nephrogenesis are controlled by precise spatiotemporal gene expression programs, which are coordinately regulated by cell-cycle, cell type-specific transcription factors and epigenetic/chromatin regulators. However, the roles of epigenetic/chromatin regulators in kidney development and disease remain poorly understood. In this study, we investigated the impact of deleting the chromatin remodeling factor Smarca4 (Brg1), a human Wilms tumor-associated gene, in Wnt4-expressing cells. Smarca4 deficiency led to severe tubular defects and a shortened medulla. Through unbiased single-cell RNA sequencing analyses, we identified multiple types of Wnt4 Cre-labeled interstitial cells, along with nephron-related cells. Smarca4 deficiency increased interstitial cells but markedly reduced tubular cells, resulting in cells with mixed identity and elevated expression of cell-cycle regulators and genes associated with extracellular matrix and epithelial-to-mesenchymal transition/fibrosis. We found that Smarca4 loss induced a significant upregulation of the oncogene Pttg1 and hyperproliferation of Wnt4 Cre-labeled cells. These changes in the cellular state could hinder the cellular transition into characteristic tubular structures, eventually leading to fibrosis. In conclusion, our findings shed light on novel cell types and genes associated with Wnt4 Cre-labeled cells and highlight the critical role of Smarca4 in regulating tubular cell differentiation and the expression of the cancer-causing gene Pttg1 in the kidney. These findings may provide valuable insights into potential therapeutic strategies for renal cell carcinoma resulting from SMARCA4 deficiency.
摘要：
肾脏的形成和肾脏发生是由精确的时空基因表达程序来控制的。受细胞周期协调调节，细胞类型特异性转录因子和表观遗传/染色质调节因子。然而,表观遗传/染色质调节因子在肾脏发育和疾病中的作用尚不清楚.在这项研究中,我们调查了删除染色质重塑因子Smarca4（Brg1）的影响，一个人类Wilms肿瘤相关基因,在表达Wnt4的细胞中。Smarca4缺乏导致严重的肾小管缺损和髓质缩短。通过无偏单细胞RNA测序分析，我们确定了多种类型的Wnt4Cre标记的间质细胞，以及与肾单位相关的细胞.Smarca4缺乏增加间质细胞，但显著减少肾小管细胞，导致细胞具有混合同一性，细胞周期调节因子和与细胞外基质和上皮间质转化/纤维化相关的基因表达升高。我们发现Smarca4丢失诱导癌基因Pttg1的显着上调和Wnt4Cre标记的细胞的过度增殖。细胞状态的这些变化可能会阻碍细胞转变为特征性的管状结构，最终导致纤维化。总之,我们的研究结果揭示了与Wnt4Cre标记细胞相关的新细胞类型和基因,并强调了Smarca4在调节肾小管细胞分化和致癌基因Pttg1表达中的关键作用.这些发现可能为SMARCA4缺乏导致的肾细胞癌的潜在治疗策略提供有价值的见解。
