TY - JOUR
T1 - HSF4 regulates DLAD expression and promotes lens de-nucleation
AU - Cui, Xiukun
AU - Wang, Lei
AU - Zhang, Jing
AU - Du, Rong
AU - Liao, Shengjie
AU - Li, Duanzhuo
AU - Li, Chang
AU - Ke, Tie
AU - Li, David Wan Cheng
AU - Huang, Hua
AU - Yin, Zhan
AU - Tang, Zhaohui
AU - Liu, Mugen
N1 - Funding Information:
This work was supported by National Natural Science Foundation of China grants # 81270983 and 31071106 (ML), 30771199 (ZT), and National Key Technology R&D Program in the 12th Five year Plan of China # 2012BAI09B00 (ML), and NIH/NEI grant 1R01EY018380 (DWL). We thank Dr. Ying Wan for refining our writing of this manuscript.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Cataract mutation
KW - DLAD
KW - HSF4
KW - Lens differentiation
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U2 - 10.1016/j.bbadis.2013.03.007
DO - 10.1016/j.bbadis.2013.03.007
M3 - Article
C2 - 23507146
AN - SCOPUS:84877354224
VL - 1832
SP - 1167
EP - 1172
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
SN - 0925-4439
IS - 8
ER -