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

Bushra Hayat; Ramani Shyam Kapuganti; Biswajit Padhy; Pranjya Paramita Mohanty; Debasmita Pankaj Alone

doi:10.1038/s10038-020-0736-8

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

Journal article

Peer reviewed

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

Bushra Hayat, Ramani Shyam Kapuganti, Biswajit Padhy, Pranjya Paramita Mohanty and Debasmita Pankaj Alone

Journal of human genetics, Vol.65(6), pp.517-529

06/01/2020

DOI: 10.1038/s10038-020-0736-8

PMID: 32127624

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Abstract

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.

Cell Culture Techniques

CpG Islands - genetics

DNA (Cytosine-5-)-Methyltransferases - genetics

DNA Methylation - genetics

Epigenesis, Genetic - genetics

Exfoliation Syndrome - genetics

Exfoliation Syndrome - pathology

Female

Gene Expression Regulation

Glaucoma - genetics

Glaucoma - pathology

HSP70 Heat-Shock Proteins - genetics

Humans

Male

Details

Title: Subtitle: Epigenetic silencing of heat shock protein 70 through DNA hypermethylation in pseudoexfoliation syndrome and glaucoma
Creators: Bushra Hayat - National Institute of Science Education and Research
Ramani Shyam Kapuganti - National Institute of Science Education and Research
Biswajit Padhy - National Institute of Science Education and Research
Pranjya Paramita Mohanty - Sri Sri Borda Hospital, Dhauli, Bhubaneswar, Odisha, 751002, India
Debasmita Pankaj Alone - National Institute of Science Education and Research
Resource Type: Journal article
Publication Details: Journal of human genetics, Vol.65(6), pp.517-529
DOI: 10.1038/s10038-020-0736-8
PMID: 32127624
ISSN: 1434-5161
eISSN: 1435-232X
Language: English
Date published: 06/01/2020
Academic Unit: Internal Medicine
Record Identifier: 9985157526702771

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