| First Author | Chan SC | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 51 | Pages | 17560-17572 |
| PubMed ID | 33453998 | Mgi Jnum | J:329514 |
| Mgi Id | MGI:6714530 | Doi | 10.1074/jbc.RA120.015592 |
| Citation | Chan SC, et al. (2020) Hepatocyte nuclear factor 1beta suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer-binding factor 1. J Biol Chem 295(51):17560-17572 |
| abstractText | Hepatocyte nuclear factor-1beta (HNF-1beta) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1beta produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1beta in mIMCD3 renal epithelial cells results in activation of beta-catenin and increased expression of lymphoid enhancer-binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1beta in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1beta binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1beta decreases H3K27 trimethylation repressive marks and increases beta-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1beta recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the beta-catenin-binding domain of LEF1 in HNF-1beta-deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1beta through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1beta regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1beta. |
