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Abstract #86336 Published in IGR 21-2

Epigenetic silencing of heat shock protein 70 through DNA hypermethylation in pseudoexfoliation syndrome and glaucoma

Hayat B; Kapuganti RS; Padhy B; Mohanty PP; Alone DP
Journal of Human Genetics 2020; 65: 517-529

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This study is intended to investigate the epigenetic regulation of the most conserved molecular chaperone, HSP70 and its potential role in the pathophysiology of pseudoexfoliation syndrome (PEXS) and glaucoma (PEXG), a protein aggregopathy, contributing significantly to world blindness. Expression levels of HSP70 were significantly decreased in the lens capsule (LC) of PEXS but not in PEXG compared with that in control. Bisulfite sequencing of the LC of the study subjects revealed that the CpG islands (CGIs) located in the exonic region but not in the promoter region of HSP70 displayed hypermethylation only in PEXS individuals. There was a corresponding increase in DNA methyltransferase 3A (DNMT3A) expression in only PEXS individuals suggesting de novo methylation in this stage of the disease condition. On the other hand, peripheral blood of both PEXS and PEXG cases showed hypermethylation in the exonic region when compared with non-PEX controls displaying tissue-specific effects. Further, functional analyses of CGI spanning the exon revealed a decreased gene expression in the presence of methylated in comparison with unmethylated reporter gene vectors. Treatment of human lens epithelial B-3 (HLE B-3) cells with DNMT inhibitor restored the expression of HSP70 following depletion in methylation level at exonic CpG sites. In conclusion, a decreased HSP70 expression correlates with hypermethylation of a CGI of HSP70 in PEXS individuals. The present findings enhance our current understanding of the mechanism underlying HSP70 repression, contributing to the pathogenesis of PEX.

School of Biological Sciences, National Institute of Science Education and Research (NISER), HBNI, P.O. Bhimpur-Padanpur, Jatni, Khurda, Bhubaneswar, Odisha, 752050, India.

Full article

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Classification:

9.4.4.1 Exfoliation syndrome (Part of: 9 Clinical forms of glaucomas > 9.4 Glaucomas associated with other ocular and systemic disorders > 9.4.4 Glaucomas associated with disorders of the lens)
3.5 Molecular biology incl. SiRNA (Part of: 3 Laboratory methods)
3.6 Cellular biology (Part of: 3 Laboratory methods)

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