PUBLICATION

Heme acts through the Bach1b/Nrf2a-MafK pathway to regulate exocrine peptidase precursor genes in porphyric zebrafish

Authors
Zhang, S., Xu, M., Huang, J., Tang, L., Zhang, Y., Wu, J., Lin, S., and Wang, H.
ID
ZDB-PUB-140325-4
Date
2014
Source
Disease models & mechanisms   7(7): 837-45 (Journal)
Registered Authors
Wang, Han
Keywords
none
MeSH Terms
  • Models, Biological
  • Signal Transduction*/drug effects
  • Signal Transduction*/genetics
  • NIH 3T3 Cells
  • Animals
  • Enzyme Precursors/genetics*
  • Enzyme Precursors/metabolism
  • Mice
  • In Situ Hybridization
  • Gene Expression Regulation/drug effects
  • Peptide Hydrolases/genetics*
  • Porphyrias, Hepatic/enzymology
  • Porphyrias, Hepatic/genetics*
  • Zebrafish/genetics*
  • Protein Multimerization
  • Heme/metabolism*
  • Heme/pharmacology
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Molecular Sequence Data
  • Promoter Regions, Genetic/genetics
  • Nucleotide Motifs/genetics
  • Chromatin Immunoprecipitation
  • Gene Knockdown Techniques
  • Pancreas, Exocrine/drug effects
  • Pancreas, Exocrine/enzymology
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
(all 31)
PubMed
24652768 Full text @ Dis. Model. Mech.
Abstract

Using a zebrafish model for hepatoerythropoietic porphyria (HEP), we found a new mechanism underlying heme regulation of exocrine zymogens. Zebrafish bach1b, nrf2a and mafK are all expressed in the zebrafish exocrine pancreas. Overexpression of bach1b and knockdown of nrf2a result in downregulation of the zymogens, whereas overexpression of nrf2a and knockdown of bach1b cause their upregulation. In vitro luciferase assays demonstrated that heme activates the zymogens in a dosage-dependent manner, and the zymogens promoter activities require the integral MARE (Maf Recognition Element) motif. The Bach1b:MafK heterodimer represses the zymogens, whilst the Nrf2a:MafK heterodimer activates them. Furthermore, chromatin immunoprecipitation (ChIP) assays showed that MafK binds the MARE sites in the 5'; regulatory regions of the zymogens, heme triggers replacing Bach1b with Nrf2a within the MafK-occupied MARE sites in the regulatory regions of the zymogens, and particularly in heme-deficient porphyria, the repressing Bach1b:MafK heterodimer dominates, which can be switched to the activating Nrf2a:MafK heterodimer by hemin treatment. These results provide novel insights into regulation of exocrine function as well as the pathogenesis of porphyria, and should be useful for designing therapies for diseases of both categories.

Genes / Markers
Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
tp61
    		Point Mutation
    1 - 1 of 1
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    Human Disease / Model
    Sequence Targeting Reagents
    Fish
    Fish
    urodtp61/tp61
    WT
    WT + MO1-bach1b
    WT + MO1-nfe2l2a
    1 - 4 of 4
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    Antibodies
    No data available
    Orthology
    Engineered Foreign Genes
    No data available
    Mapping
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    Citation
    Zhang, S., Xu, M., Huang, J., Tang, L., Zhang, Y., Wu, J., Lin, S., and Wang, H. (2014) Heme acts through the Bach1b/Nrf2a-MafK pathway to regulate exocrine peptidase precursor genes in porphyric zebrafish. Disease models & mechanisms. 7(7):837-45.