PDF(Pubmed)
Abstract：
How disruptions to normal cell differentiation link to tumorigenesis remains incompletely understood. Wilms tumor, an embryonal tumor associated with disrupted organogenesis, often harbors mutations in epigenetic regulators, but their role in kidney development remains unexplored. Here, we show at single-cell resolution that a Wilms tumor-associated mutation in the histone acetylation reader ENL disrupts kidney differentiation in mice by rewiring the gene regulatory landscape. Mutant ENL promotes nephron progenitor commitment while restricting their differentiation by dysregulating transcription factors such as Hox clusters. It also induces abnormal progenitors that lose kidney-associated chromatin identity. Furthermore, mutant ENL alters the transcriptome and chromatin accessibility of stromal progenitors, resulting in hyperactivation of Wnt signaling. The impacts of mutant ENL on both nephron and stroma lineages lead to profound kidney developmental defects and postnatal mortality in mice. Notably, a small molecule inhibiting mutant ENL\'s histone acetylation binding activity largely reverses these defects. This study provides insights into how mutations in epigenetic regulators disrupt kidney development and suggests a potential therapeutic approach.
摘要：
对正常细胞分化的破坏如何与肿瘤发生联系仍未完全了解。肾母细胞瘤，与器官发生破坏相关的胚胎性肿瘤，通常在表观遗传调节因子中存在突变，但它们在肾脏发育中的作用仍有待探索。这里,我们以单细胞分辨率显示,组蛋白乙酰化读数器ENL中的Wilms肿瘤相关突变通过重新连接基因调控格局破坏小鼠肾脏分化.突变体ENL促进肾单位祖细胞的承诺，同时通过失调转录因子如Hox簇限制其分化。它还诱导失去肾脏相关染色质同一性的异常祖细胞。此外，突变型ENL改变了基质祖细胞的转录组和染色质可及性，导致Wnt信号的过度激活。突变型ENL对肾单位和基质谱系的影响导致小鼠严重的肾脏发育缺陷和出生后死亡。值得注意的是,抑制突变体ENL的组蛋白乙酰化结合活性的小分子在很大程度上逆转了这些缺陷。这项研究提供了有关表观遗传调节因子突变如何破坏肾脏发育的见解，并提出了一种潜在的治疗方法。
