HSF4 regulates DLAD expression and promotes lens de-nucleation

Xiukun Cui, Lei Wang, Jing Zhang, Rong Du, Shengjie Liao, Duanzhuo Li, Chang Li, Tie Ke, David Wan Cheng Li, Hua Huang, Zhan Yin, Zhaohui Tang, Mugen Liu

Research output: Contribution to journalArticle

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1167-1172
Number of pages6
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1832
Issue number8
DOIs
StatePublished - 2013

Keywords

  • Cataract mutation
  • DLAD
  • HSF4
  • Lens differentiation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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  • Cite this

    Cui, X., Wang, L., Zhang, J., Du, R., Liao, S., Li, D., Li, C., Ke, T., Li, D. W. C., Huang, H., Yin, Z., Tang, Z., & Liu, M. (2013). HSF4 regulates DLAD expression and promotes lens de-nucleation. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1832(8), 1167-1172. https://doi.org/10.1016/j.bbadis.2013.03.007