肾脏形成和肾发育受到精确的时空基因表达程序的调控，这些程序由细胞周期、细胞类型特异性转录因子以及表观遗传/染色质调控因子协调调控。然而，表观遗传/染色质调控因子在肾发育和疾病中的作用仍然知之甚少。在本研究中，我们调查了在表达Wnt4的细胞中删除染色质重塑因子Smarca4（Brg1），即人类儿茶酚胺肿瘤关联基因，的影响。Smarca4缺陷导致严重的小管缺陷和髓质缩短。通过无偏单细胞RNA测序分析，我们鉴定了多种类型的Wnt4 Cre标记的间质细胞以及肾单位相关细胞。Smarca4缺陷增加了间质细胞，但明显减少了小管细胞，导致细胞身份混合和细胞周期调控因子的表达和与细胞外基质、上皮间质转化/纤维化有关的基因的显著增加。我们发现，Smarca4缺失显著上调了癌基因Pttg1的表达，并导致Wnt4 Cre标记细胞的过度增殖。这些细胞状态的改变可能阻碍了细胞向特征性小管结构的过渡，最终导致纤维化。总之，我们的研究结果揭示了与Wnt4 Cre标记细胞相关的新的细胞类型和基因，并强调了Smarca4在调控小管细胞分化以及癌基因Pttg1的表达中的关键作用。这些发现可能为SMARCA4缺陷导致的肾细胞癌潜在治疗策略提供了有价值的见解。版权所有 © 2023 Xu，Zhou，Zhang，Zhang和Xu。

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.Copyright © 2023 Xu, Zhou, Zhang, Zhang and Xu.