A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells
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.
Copyright and License
© 2021, Guo et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Funding
Andrew P McMahon: National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK054364 Cell Interaction in Development of the Mammalian Kidney)
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Contributions
Qiuyu Guo, Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing; Albert Kim, Conceptualization, Formal analysis, Validation, Investigation, Visualization, Methodology; Bin Li, Data curation, Formal analysis, Methodology; Andrew Ransick, Data curation, Formal analysis, Investigation, Methodology; Helena Bugacov, Writing - review and editing; Xi Chen, Nils Lindström, Bing Ren, Methodology, Writing - review and editing; Aaron Brown, Resources, Methodology; Leif Oxburgh, Resources, Methodology, Writing - review and editing; Andrew P McMahon, Conceptualization, Supervision, Funding acquisition, Writing - review and editing
Data Availability
All RNA-Seq, ATAC-Seq, ChIP-Seq and HiC data sets are accessible through GEO (GSE131119).
Guo Q, Kim AD, McMahon AP (2021) NCBI Gene Expression Omnibus ID GSE131119. Genome-wide map of open chromatin, trancription factor occupancy, chromatin marks and gene expression profiles in mouse nephron progenitor cells. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE131119
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#11893) of the University of Southern California. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Southern California. Every effort was made to minimize suffering.
Errata
Correction: A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells. (Feb 15, 2021, https://doi.org/10.7554/eLife.64444)
Guo Q, Kim A, Li B, Ransick A, Bugacov H, Chen X, Lindström N, Brown A, Oxburgh L, Ren B, McMahon AP. 2021. A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells. eLife 10:e64444. doi: 10.7554/eLife.64444.
We overlooked an important published study by Ramalingam et al (2018) which draws the conclusion that different levels of ß-catenin, resulting from different levels of Wnt9b ligand, determine nephron progenitor cell (NPC) outcomes. Though our study focuses on defined NPC cultures and genomic interactions amongst ß-catenin and Tcf/Lef transcriptional mediators that were not explored in Ramalingham et al., our approaches agree on the importance of ß-catenin levels in modifying the state of NPCs. Accordingly, we have corrected our manuscript below to acknowledge Ramalingam et al (2018) were appropriate and we apologize to the authors for the oversight.
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Additional details
- National Institute of Diabetes and Digestive and Kidney Diseases
- Cell Interaction in Development of the Mammalian Kidney R01 DK054364
- Accepted
-
2021-02-15Accepted
- Available
-
2021-03-01Version of record
- Available
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2021-04-29Version of record
- Caltech groups
- Division of Biology and Biological Engineering
- Publication Status
- Published