Pluto Bioinformatics

GSE130164: Hepatocyte nuclear factor-1 regulates Wnt signaling through genome-wide competition with -catenin/lymphoid enhancer binding factor

Bulk RNA sequencing

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