PUBLICATION
Deficiency of Heat shock factor 4 promotes lens epithelial cell senescence through upregulating p21cip1 expression
- Authors
- Cui, X., Du, C., Wan, S., Wu, D., Yan, L., Zhang, J., Li, J., Li, H., Yang, Z., Zhang, H., Zhang, J., Mu, H., Zhang, F., Peng, X., Liu, M., Hu, Y.
- ID
- ZDB-PUB-210803-14
- Date
- 2021
- Source
- Biochimica et biophysica acta. Molecular basis of disease 1867(11): 166233 (Journal)
- Registered Authors
- Cui, Xiukun, Hu, Yanzhong, Zhang, Jing
- Keywords
- H3K27m3, HSF4, cellular senescence, ocular lens, p21(cip1), transcription
- MeSH Terms
-
- Aging/genetics
- Animals
- Animals, Genetically Modified
- Cataract/genetics
- Cataract/pathology
- Cell Line
- Cellular Senescence/genetics
- Cellular Senescence/radiation effects
- Cyclin-Dependent Kinase Inhibitor p21/genetics*
- DNA Methylation
- Disease Models, Animal
- Enhancer of Zeste Homolog 2 Protein/metabolism
- Epithelial Cells/pathology
- Epithelial Cells/radiation effects
- Gene Expression Regulation, Developmental
- Gene Knockout Techniques
- Heat Shock Transcription Factors/deficiency*
- Heat Shock Transcription Factors/genetics
- Histones/genetics
- Histones/metabolism
- Humans
- Lens, Crystalline/cytology
- Lens, Crystalline/growth & development
- Lens, Crystalline/pathology*
- Lens, Crystalline/radiation effects
- Mice
- Promoter Regions, Genetic
- Ultraviolet Rays/adverse effects
- Zebrafish
- Zebrafish Proteins/deficiency*
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 34339841 Full text @ BBA Molecular Basis of Disease
Citation
Cui, X., Du, C., Wan, S., Wu, D., Yan, L., Zhang, J., Li, J., Li, H., Yang, Z., Zhang, H., Zhang, J., Mu, H., Zhang, F., Peng, X., Liu, M., Hu, Y. (2021) Deficiency of Heat shock factor 4 promotes lens epithelial cell senescence through upregulating p21cip1 expression. Biochimica et biophysica acta. Molecular basis of disease. 1867(11):166233.
Abstract
Genetic mutations in heat shock factor 4 (Hsf4) is associated with both congenital and age-related cataracts. Hsf4 regulates lens development through its ability to both activate and inhibit transcription. Previous studies suggested Hsf4 is involved in modulating cellular senescence depending on p21cip1 and p27 kip1 expression in MEF cells. Here, we found that Hsf4 acts as a suppressor of p21cip1 expression and plays an anti-senescence role during lens development. Knocking out Hsf4 facilitated UVB-induced cellular senescence in mouse lens epithelial cells (mLECs). p21cip1 was upregulated at both the mRNA and protein levels in HSF4-/- mLECs under control and UVB-treated conditions, and knockdown of p21cip1 by siRNA alleviated UVB-induced cellular senescence. HSF4 directly bound to the p21cip1 promoter and increased H3K27m3 levels at the p21cip1 proximal promoter region by recruiting the methyltransferase EZH2. In animal models, p21cip1 was gradually upregulated in wild-type mouse lenses with increasing age, while Hsf4 levels decreased. We generated a Hsf4 mutant mice line (Hsf4del-42) which displayed obvious congenital cataract phenotype. The expression of p21cip1 and senescence-associated cytokines were induced in the cataractous lenses of Hsf4del-42 mice. H3K27m3 and EZH2 levels decreased in p21cip1 promoters in the lenses of Hsf4del-42 mice. The SA-β-Gal activities was positive in lens epithelia of aged Hsf4null zebrafish compared to wild-type lenses. p21cip1 and senescence-associated cytokines levels were also upregulated in lenses of Hsf4null zebrafish. Accordingly, we propose that HSF4 plays a protective role in lens epithelial cells against cellular senescence during lens development and aging, partly by fine-tuning p21cip1 expression.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping