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

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

The Journal of biological chemistry, 2020-10, Vol.295 (51), p.17560-17572 [Periódico revisado por pares]

11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A: American Society for Biochemistry and Molecular Biology

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  • Título:
    Hepatocyte nuclear factor 1β suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer–binding factor 1
  • Autor: Chan, Siu Chiu ; Hajarnis, Sachin S. ; Vrba, Sophia M. ; Patel, Vishal ; Igarashi, Peter
  • Assuntos: Gene Regulation
  • É parte de: The Journal of biological chemistry, 2020-10, Vol.295 (51), p.17560-17572
  • Notas: Present address for Sachin S. Hajarnis: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey, USA.
    Edited by Eric R. Fearon
    Present address for Sophia M. Vrba: Laboratory of Clinical Immunology and Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland, USA.
  • Descrição: 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.
  • Editor: 11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A: American Society for Biochemistry and Molecular Biology
  • Idioma: Inglês
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