PUBLICATION

HSF4 regulates DLAD expression and promotes lens de-nucleation

Authors
Cui, X., Wang, L., Zhang, J., Du, R., Liao, S., Li, D., Li, C., Ke, T., Li, D.W., Huang, H., Yin, Z., Tang, Z., and Liu, M.
ID
ZDB-PUB-130405-21
Date
2013
Source
Biochimica et biophysica acta. Molecular basis of disease   1832(8): 1167-72 (Journal)
Registered Authors
Liu, Mugen, Yin, Zhan, Zhang, Jing
Keywords
HSF4, cataract mutation, DLAD, lens differentiation
MeSH Terms
  • Animals
  • Cataract/genetics
  • Cataract/metabolism
  • Cataract/physiopathology*
  • Cell Differentiation/genetics
  • Cell Differentiation/physiology
  • Cell Nucleus/genetics
  • Cell Nucleus/metabolism
  • Cell Nucleus/physiology
  • Cells, Cultured
  • DNA/genetics
  • DNA-Binding Proteins/genetics
  • DNA-Binding Proteins/metabolism*
  • Endodeoxyribonucleases/biosynthesis*
  • Endodeoxyribonucleases/genetics
  • Endodeoxyribonucleases/metabolism
  • Epithelial Cells/metabolism
  • Epithelial Cells/physiology
  • Humans
  • Lens, Crystalline/metabolism
  • Lens, Crystalline/physiology*
  • Mutation
  • Promoter Regions, Genetic
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
  • Zebrafish
PubMed
23507146 Full text @ BBA Molecular Basis of Disease
Abstract

HSF4 mutations lead to both congenital and age-related cataract. The purpose of this study was to explore the mechanism of cataract formation caused by HSF4 mutations. The degradation of nuclear DNA is essential for the lens fiber differentiation. DNase 2β (DLAD) is highly expressed in lens cells, and mice with deficiencies in the DLAD gene develop nuclear cataracts. In this study, we found that HSF4 promoted the expression and DNase activity of DLAD by directly binding to the DLAD promoter. In contrast, HSF4 cataract causative mutations failed to bind to the DLAD promoter, abrogating the expression and DNase activity of DLAD. These results were confirmed by HSF4 knockdown in zebrafish, which led to incomplete de-nucleation of the lens and decreased expression and activity of DLAD. Together, our results suggest that HSF4 exerts its function on lens differentiation via positive regulation of DLAD expression and activity, thus facilitating de-nucleation of lens fiber cells. Our demonstration that HSF4 cataract causative mutations abrogate the induction of DLAD expression reveals a novel molecular mechanism regarding how HSF4 mutations cause cataractogenesis.

Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping