Hepatocyte nuclear factor-1β regulates Wnt signaling through genome-wide competition with β-catenin/ lymphoid enhancer binding factor

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Abstract

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is essential for normal kidney development and renal tubular function. Mutations of HNF-1β produce cystic kidney disease, a phenotype associated with deregulation of canonical (β-catenin–dependent) Wnt signaling. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells produces hyperresponsiveness to Wnt ligands and increases expression of Wnt target genes, including Axin2, Ccdc80, and Rnf43. Levels of β-catenin and expression of Wnt target genes are also increased in HNF-1β mutant mouse kidneys. Genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) in wild-type and mutant cells showed that ablation of HNF-1β increases by 6-fold the number of sites on chromatin that are occupied by β-catenin. Remarkably, 50% of the sites that are occupied by β-catenin in HNF-1β mutant cells colocalize with HNF-1β–occupied sites in wild-type cells, indicating widespread reciprocal binding. We found that the Wnt target genes Ccdc80 and Rnf43 contain a composite DNA element comprising a β-catenin/lymphoid enhancer binding factor (LEF) site overlapping with an HNF-1β half-site. HNF-1β and β-catenin/LEF compete for binding to this element, and thereby HNF-1β inhibits β-catenin–dependent transcription. Collectively, these studies reveal a mechanism whereby a transcription factor constrains canonical Wnt signaling through direct inhibition of β-catenin/LEF chromatin binding.

Original languageEnglish (US)
Pages (from-to)24133-24142
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number48
DOIs
StatePublished - Nov 26 2019

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Svetlana Avdulov for technical assistance, Mark Murphy, and Micah Gearhart for advice on ChIP and EMSA, Colleen Forster for histology support and consultation (Bionet, Clinical and Translational Science Institute, University of Minnesota), and Sachin Hajarnis for performing the preliminary studies on this project. Illumina sequencing services were performed by the University of Minnesota Genomics Center, and the Minnesota Supercomputing Institute provided bioinformatic, software support, and data storage. This work was supported by NIH Grant R37DK042921 (to P.I.).

Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.

Keywords

  • Developmen
  • Kidney
  • T |
  • Transcription
  • Wnt |
  • | polycystic kidney disease |
  • β-catenin

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