Hepatocyte nuclear factor 1b suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer–binding factor 1

Siu Chiu Chan, Sachin S. Hajarnis, Sophia M. Vrba, Vishal Patel, Peter Igarashi

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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

Original languageEnglish (US)
Pages (from-to)17560-17572
Number of pages13
JournalJournal of Biological Chemistry
Issue number51
StatePublished - Dec 18 2020

Bibliographical note

Funding Information:
Funding and additional information—This work was supported by the NIDDK, National Institutes of Health Grant R37DK042921 (to P. I.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2020 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.


Dive into the research topics of 'Hepatocyte nuclear factor 1b suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer–binding factor 1'. Together they form a unique fingerprint.

Cite this