A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells
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. Lo...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/64444 |
| _version_ | 1811200368313368576 |
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| author | Qiuyu Guo Albert Kim Bin Li Andrew Ransick Helena Bugacov Xi Chen Nils Lindström Aaron Brown Leif Oxburgh Bing Ren Andrew P McMahon |
| author_facet | Qiuyu Guo Albert Kim Bin Li Andrew Ransick Helena Bugacov Xi Chen Nils Lindström Aaron Brown Leif Oxburgh Bing Ren Andrew P McMahon |
| author_sort | Qiuyu Guo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:03:43Z |
| format | Article |
| id | doaj.art-7d32c02571314e02b93a28cc51a1cb85 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:03:43Z |
| publishDate | 2021-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7d32c02571314e02b93a28cc51a1cb852022-12-22T03:52:36ZengeLife Sciences Publications LtdeLife2050-084X2021-02-011010.7554/eLife.64444A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cellsQiuyu Guo0https://orcid.org/0000-0001-8549-8335Albert Kim1Bin Li2Andrew Ransick3Helena Bugacov4Xi Chen5Nils Lindström6Aaron Brown7Leif Oxburgh8Bing Ren9Andrew P McMahon10https://orcid.org/0000-0002-3779-1729Department 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 StatesDepartment 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 StatesThe Rogosin Institute, New York, United StatesDepartment 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 StatesDepartment 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 StatesDepartment 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 StatesDepartment 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 StatesCenter for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, United StatesThe Rogosin Institute, New York, United StatesLudwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, Moores Cancer Center, University of California San Diego, San Diego, United StatesDepartment 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 StatesThe 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.https://elifesciences.org/articles/64444kidney developmentstem cellsWnt signalingTCF/LEF factorstranscriptional regulation |
| spellingShingle | Qiuyu Guo Albert Kim Bin Li Andrew Ransick Helena Bugacov Xi Chen Nils Lindström Aaron Brown Leif Oxburgh Bing Ren Andrew P McMahon A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells eLife kidney development stem cells Wnt signaling TCF/LEF factors transcriptional regulation |
| title | A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells |
| title_full | A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells |
| title_fullStr | A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells |
| title_full_unstemmed | A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells |
| title_short | A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells |
| title_sort | β catenin driven switch in tcf lef transcription factor binding to dna target sites promotes commitment of mammalian nephron progenitor cells |
| topic | kidney development stem cells Wnt signaling TCF/LEF factors transcriptional regulation |
| url | https://elifesciences.org/articles/64444 |
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