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

  1. Qiuyu Guo
  2. Albert D Kim
  3. Bin Li
  4. Andrew Ransick
  5. Helena Bugacov
  6. Xi Chen
  7. Nils O Lindström
  8. Aaron Brown
  9. Leif Oxburgh
  10. Bing Ren
  11. Andrew P McMahon  Is a corresponding author
  1. University of California, Los Angeles, United States
  2. 10x Genomics, United States
  3. University of California, San Diego, United States
  4. Keck School of Medicine of the University of Southern California, United States
  5. Maine Medical Center Research Institute, United States
  6. The Rogosin Institute, United States

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 CHIR9902 (CHIR) to examine opposing developmental actions of β-catenin. Low CHIR-mediated maintenance and expansion of NPCs is 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.

Data availability

All RNA-Seq, ATAC-Seq, ChIP-Seq and HiC data sets are accessible through GEO (GSE131119).

The following data sets were generated

Article and author information

Author details

  1. Qiuyu Guo

    Neurology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Albert D Kim

    Sample Preparation, 10x Genomics, Pleasanton, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Bin Li

    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Andrew Ransick

    Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Biology, Keck School of Medicine of the University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Helena Bugacov

    Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Biology, Keck School of Medicine of the University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xi Chen

    Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Biology, Keck School of Medicine of the University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Nils O Lindström

    Department of Stem Cell Biology and Regenerative Medicine, Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Aaron Brown

    Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Leif Oxburgh

    The Rogosin Institute, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Bing Ren

    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Andrew P McMahon

    Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Biology, Keck School of Medicine of the University of Southern California, Los Angeles, United States
    For correspondence
    amcmahon@med.usc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3779-1729

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK054364 Cell Interaction in Development of the Mammalian Kidney)

  • Andrew P McMahon

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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.

Reviewing Editor

  1. Edward E Morrisey, University of Pennsylvania, United States

Publication history

  1. Received: October 29, 2020
  2. Accepted: February 14, 2021
  3. Accepted Manuscript published: February 15, 2021 (version 1)
  4. Version of Record published: March 1, 2021 (version 2)
  5. Version of Record updated: April 29, 2021 (version 3)

Copyright

© 2021, Guo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Qiuyu Guo
  2. Albert D Kim
  3. Bin Li
  4. Andrew Ransick
  5. Helena Bugacov
  6. Xi Chen
  7. Nils O Lindström
  8. Aaron Brown
  9. Leif Oxburgh
  10. Bing Ren
  11. Andrew P McMahon
(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.
https://doi.org/10.7554/eLife.64444

Further reading

    1. Developmental Biology
    Marianne E Emmert, Parul Aggarwal ... Roger Cornwall
    Research Article Updated

    Neonatal brachial plexus injury (NBPI) causes disabling and incurable muscle contractures that result from impaired longitudinal growth of denervated muscles. This deficit in muscle growth is driven by increased proteasome-mediated protein degradation, suggesting a dysregulation of muscle proteostasis. The myostatin (MSTN) pathway, a prominent muscle-specific regulator of proteostasis, is a putative signaling mechanism by which neonatal denervation could impair longitudinal muscle growth, and thus a potential target to prevent NBPI-induced contractures. Through a mouse model of NBPI, our present study revealed that pharmacologic inhibition of MSTN signaling induces hypertrophy, restores longitudinal growth, and prevents contractures in denervated muscles of female but not male mice, despite inducing hypertrophy of normally innervated muscles in both sexes. Additionally, the MSTN-dependent impairment of longitudinal muscle growth after NBPI in female mice is associated with perturbation of 20S proteasome activity, but not through alterations in canonical MSTN signaling pathways. These findings reveal a sex dimorphism in the regulation of neonatal longitudinal muscle growth and contractures, thereby providing insights into contracture pathophysiology, identifying a potential muscle-specific therapeutic target for contracture prevention, and underscoring the importance of sex as a biological variable in the pathophysiology of neuromuscular disorders.