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β-连环蛋白驱动的 TCF/LEF 转录因子与 DNA 靶位点结合的开关促进哺乳动物肾祖细胞的定型。

A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells.

机构信息

Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, United States.

The Rogosin Institute, New York, United States.

出版信息

Elife. 2021 Feb 15;10:e64444. doi: 10.7554/eLife.64444.

DOI:10.7554/eLife.64444
PMID:33587034
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7924951/
Abstract

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.

摘要

经典 Wnt 通路转录共激活因子β-连环蛋白调控哺乳动物肾祖细胞 (NPC) 的自我更新和分化。我们使用 GSK3 抑制剂 CHIR99021 (CHIR) 调节 NPC 培养物中的β-连环蛋白水平，以研究β-连环蛋白的相反发育作用。低 CHIR 介导的 NPC 的维持和扩增与低 CHIR 依赖性细胞周期靶标处 TCF/LEF/β-连环蛋白转录复合物的直接参与无关。相比之下，在高 CHIR 中，TCF7/LEF1/β-连环蛋白复合物取代了促进分化的靶基因增强子上的 TCF7L1/TCF7L2 结合。染色体确认研究表明，在 NPC 中，这些靶基因的启动子-增强子连接是预先建立的。在对经典 Wnt 通路的正向转录反馈调节中观察到高 CHIR 相关的从头环化。因此，β-连环蛋白的直接转录作用仅限于 NPC 的诱导，其中β-连环蛋白水平的升高将抑制性 TCF7L1/TCF7L2 复合物转换为激活的 LEF1/TCF7 复合物，在准备好快速启动肾发生程序的靶基因上。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/5f4678251da9/elife-64444-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/15e4261ac78a/elife-64444-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/206457e77a85/elife-64444-fig3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/5c4e18c1d6b9/elife-64444-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/d576bfce2f92/elife-64444-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/a7ce351b7661/elife-64444-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/bd69998561b3/elife-64444-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/3af2ca9c9ed5/elife-64444-fig4-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/d7ccf3e1f97c/elife-64444-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/5f4678251da9/elife-64444-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/15e4261ac78a/elife-64444-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/bd1f22842c84/elife-64444-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/75e21ffb1b18/elife-64444-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/6cb41c3fb6f8/elife-64444-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/206457e77a85/elife-64444-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/b5e55907e13a/elife-64444-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/5c4e18c1d6b9/elife-64444-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/d576bfce2f92/elife-64444-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/a7ce351b7661/elife-64444-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/bd69998561b3/elife-64444-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/3af2ca9c9ed5/elife-64444-fig4-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/d7ccf3e1f97c/elife-64444-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ed7/7924951/5f4678251da9/elife-64444-fig5-figsupp1.jpg

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