Hepatocyte nuclear factor 1β suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer-binding factor 1

• Published in: The Journal of biological chemistry Vol. 295; no. 51; p. 17560
• Main Authors: Chan, Siu Chiu, Hajarnis, Sachin S, Vrba, Sophia M, Patel, Vishal, Igarashi, Peter
• Format: Journal Article
• Language: English
• Published: United States 18-12-2020
• Subjects: Animals; Axin Protein - genetics; Axin Protein - metabolism; beta Catenin - metabolism; Binding Sites; Epithelial Cells - cytology; Epithelial Cells - metabolism; Gene Expression Regulation; Hepatocyte Nuclear Factor 1-beta - deficiency; Hepatocyte Nuclear Factor 1-beta - genetics; Hepatocyte Nuclear Factor 1-beta - metabolism; Histones - metabolism; Kidney - cytology; Lymphoid Enhancer-Binding Factor 1 - antagonists & inhibitors; Lymphoid Enhancer-Binding Factor 1 - genetics; Lymphoid Enhancer-Binding Factor 1 - metabolism; Methylation; Mice; Mice, Knockout; Mutagenesis; Promoter Regions, Genetic; Regulatory Elements, Transcriptional - genetics; RNA Interference; RNA, Small Interfering - metabolism; Wnt Signaling Pathway; Wnt3A Protein - metabolism; histone methylation; kidney; β-catenin; Wnt pathway; HNF-1β; LEF1; T-cell factor (TCF); cystic kidney disease; transcription repressor; beta-catenin (B-catenin); tissue-specific transcription factor
• ISSN: 1083-351X
• DOI: 10.1074/jbc.RA120.015592

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-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-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin-binding domain of LEF1 in HNF-1β-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-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β 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-1β.