| First Author | Chan SC | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 48 | Pages | 24133-24142 |
| PubMed ID | 31712448 | Mgi Jnum | J:290404 |
| Mgi Id | MGI:6436204 | Doi | 10.1073/pnas.1909452116 |
| Citation | Chan SC, et al. (2019) Hepatocyte nuclear factor-1beta regulates Wnt signaling through genome-wide competition with beta-catenin/lymphoid enhancer binding factor. Proc Natl Acad Sci U S A 116(48):24133-24142 |
| abstractText | Hepatocyte nuclear factor-1beta (HNF-1beta) is a tissue-specific transcription factor that is essential for normal kidney development and renal tubular function. Mutations of HNF-1beta produce cystic kidney disease, a phenotype associated with deregulation of canonical (beta-catenin-dependent) Wnt signaling. Here, we show that ablation of HNF-1beta in mIMCD3 renal epithelial cells produces hyperresponsiveness to Wnt ligands and increases expression of Wnt target genes, including Axin2, Ccdc80, and Rnf43 Levels of beta-catenin and expression of Wnt target genes are also increased in HNF-1beta mutant mouse kidneys. Genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) in wild-type and mutant cells showed that ablation of HNF-1beta increases by 6-fold the number of sites on chromatin that are occupied by beta-catenin. Remarkably, 50% of the sites that are occupied by beta-catenin in HNF-1beta mutant cells colocalize with HNF-1beta-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 beta-catenin/lymphoid enhancer binding factor (LEF) site overlapping with an HNF-1beta half-site. HNF-1beta and beta-catenin/LEF compete for binding to this element, and thereby HNF-1beta inhibits beta-catenin-dependent transcription. Collectively, these studies reveal a mechanism whereby a transcription factor constrains canonical Wnt signaling through direct inhibition of beta-catenin/LEF chromatin binding. |
