title: HSF4 regulates DLAD expression and promotes lens de-nucleation.
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.
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
authors.forename: Xiukun
authors.initials: X
authors.lastname: Cui
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Du
authors.forename: Shengjie
authors.initials: S
authors.lastname: Liao
authors.forename: Duanzhuo
authors.initials: D
authors.lastname: Li
authors.forename: Chang
authors.initials: C
authors.lastname: Li
authors.forename: Tie
authors.initials: T
authors.lastname: Ke
authors.forename: David Wan-Cheng
authors.initials: DW
authors.lastname: Li
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yin
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Tang
authors.forename: Mugen
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D002386:Cataract / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D000076249:Heat Shock Transcription Factors; D006801:Humans; D007908:Lens, Crystalline / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D004268:DNA-Binding Proteins; C102948:HSF4 protein, human; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D004247:DNA; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II