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

Abstract

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. Wild-type HNF-1β binds to two evolutionarily conserved sites located 94 kb 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, wild-type 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.

Cysteine and glycine‐rich protein 2 promotes hypoxic pulmonary vascular smooth muscle cell proliferation through the Wnt3α‐β‐catenin/lymphoid enhancer‐binding factor 1 pathway

“…[15,30] Although a study showed that Wnt3α/β-catenin was involved in IN-17-induced proliferation, angiogenesis, and adhesion in HPAECs, [31,32] there were no other reports about the Wnt3α/β-catenin pathway in PASMCs. In this study, we found that Wnt3α/β-catenin promoted the proliferation LEF1 is the nuclear binding partner of β-catenin, [33][34][35][36][37] which bands with β-catenin and initiates the transcription of Wnt target genes. [38] LEF1 regulates cell growth and differentiation, while the abnormal expression of LEF1 is associated with tumorigenesis, cancer cell proliferation, migration, and invasion.…”

Identification of a core transcriptional program driving the human renal mesenchymal-to-epithelial transition

“…Accordingly, studies of mutant mice with kidney-specific deletion of HNF1B showed that early steps of renal MET are unaffected by HNF1B loss, with defects instead observed at comma-and S-shaped body stages, consistent with a role for HNF1B in the completion but not initiation of MET (Massa et al, 2013). HNF1B has also been reported to antagonise Wnt/b-Catenin signalling by both directly repressing LEF1 gene expression and by competitively binding and antagonising TCF/LEF1-target genes (Chan et al, 2020;Chan et al, 2019). Increased expression of HNF1B, for example by direct activation by PAX8 as we observed, could thus provide another possible feedback mechanism to limit Wnt/b-Catenin signalling during renal MET.…”

Sexually dimorphic renal expression ofKlothois directed by a kidney-specific distal enhancer responsive to HNF1b

“…In fact, while the literature indicates potential HNF1b target genes and discusses its importance, there are only a few examples of validated HNF1b-enhancer interactions. It was reported to directly bind to regulatory elements in Lef1 and Axin2 gene loci in vitro ( 61 ), and several more targets were indicated in a Xenopus model (62). HNF1b itself is regulated by a Pax-8-responsive enhancer, and thus might be a promising target in a subsequent study (63).…”