A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells.
A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells.
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DOI：
10.7554/elife.64444
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发表时间：
2021-02-15
期刊：
影响因子：
7.7
通讯作者：
McMahon AP
中科院分区：
文献类型：
--
作者：
Guo Q;Kim A;Li B;Ransick A;Bugacov H;Chen X;Lindström N;Brown A;Oxburgh L;Ren B;McMahon AP
经典Wnt通路转录共激活因子β-catenin调节哺乳动物肾单位祖细胞（NPC）的自我更新和分化。我们使用GSK 3抑制剂CHIR 99021（CHIR）调节NPC培养物中的β-连环蛋白水平，以检查β-连环蛋白的相反发育作用。低CHIR介导的NPC维持和扩增不依赖于TCF/LEF/β-连环蛋白转录复合物在低CHIR依赖性细胞周期靶点的直接参与。相比之下，在高CHIR中，TCF 7/LEF 1/β-catenin复合物取代了TCF 7 L1/TCF 7 L2结合在促进分化的靶基因的增强子上。染色体确认研究表明，预先建立的启动子-增强子连接到这些靶基因的NPC。在对经典Wnt通路的正转录反馈调节中观察到高CHIR相关的从头循环。因此，β-连环蛋白的直接转录作用仅限于诱导NPC，其中升高的β-连环蛋白水平将抑制性TCF 7 L1/TCF 7 L2复合物转换为激活LEF 1/TCF 7复合物，其位于准备快速启动肾发生程序的启动基因靶点。
The canonical Wnt pathway transcriptional co-activator β-catenin regulates self-renewal and differentiation of mammalian nephron progenitor cells (NPCs). We modulated β-catenin levels in NPC cultures using the GSK3 inhibitor CHIR99021 (CHIR) to examine opposing developmental actions of β-catenin. Low CHIR-mediated maintenance and expansion of NPCs are independent of direct engagement of TCF/LEF/β-catenin transcriptional complexes at low CHIR-dependent cell-cycle targets. In contrast, in high CHIR, TCF7/LEF1/β-catenin complexes replaced TCF7L1/TCF7L2 binding on enhancers of differentiation-promoting target genes. Chromosome confirmation studies showed pre-established promoter–enhancer connections to these target genes in NPCs. High CHIR-associated de novo looping was observed in positive transcriptional feedback regulation to the canonical Wnt pathway. Thus, β-catenin’s direct transcriptional role is restricted to the induction of NPCs, where rising β-catenin levels switch inhibitory TCF7L1/TCF7L2 complexes to activating LEF1/TCF7 complexes at primed gene targets poised for rapid initiation of a nephrogenic program.