Pseudoexfoliation and Alzheimer's associated CLU risk variant, rs2279590, lies within an enhancer element and regulates CLU, EPHX2 and PTK2B gene expression

Biswajit Padhy; Bushra Hayat; Gargi Gouranga Nanda; Pranjya Paramita Mohanty; Debasmita Pankaj Alone

doi:10.1093/hmg/ddx329

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Pseudoexfoliation and Alzheimer's associated CLU risk variant, rs2279590, lies within an enhancer element and regulates CLU, EPHX2 and PTK2B gene expression

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Pseudoexfoliation and Alzheimer's associated CLU risk variant, rs2279590, lies within an enhancer element and regulates CLU, EPHX2 and PTK2B gene expression

Biswajit Padhy, Bushra Hayat, Gargi Gouranga Nanda, Pranjya Paramita Mohanty and Debasmita Pankaj Alone

Human molecular genetics, Vol.26(22), pp.4519-4529

11/15/2017

DOI: 10.1093/hmg/ddx329

PMID: 28973302

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Abstract

Genetic variants at PTK2B-CLU locus pose as high-risk factors for many age-related disorders. However, the role of these variants in disease progression is less characterized. In this study, we aimed to investigate the functional significance of a clusterin intronic SNP, rs2279590, that has been associated with pseudoexfoliation, Alzheimer's disease (AD) and diabetes. We have previously shown that the alleles at rs2279590 differentially regulate clusterin (CLU) gene expression in lens capsule tissues. This polymorphism resides in an active regulatory region marked by H3K27Ac and DNase I hypersensitive site and is an eQTL for CLU expression. Here, we report the presence of an enhancer element in surrounding region of rs2279590. Deletion of a 115 bp intronic region flanking the rs2279590 variant through CRISPR-Cas9 genome editing in HEK293 cells demonstrated a decreased clusterin gene expression. Electrophoretic mobility shift and chromatin immunoprecipitation assays show that rs2279590 with allele 'A' constitutes a transcription factor binding site for heat shock factor-1 (HSF1) but not with allele 'G'. By binding to allele 'A', HSF1 abrogates the enhancer effect of the locus as validated by reporter assays. Interestingly, rs2279590 locus has a widespread enhancer effect on two nearby genes, protein tyrosine kinase 2 beta (PTK2B) and epoxide hydrolase-2 (EPHX2); both of which have been previously associated with AD as risk factors. To summarize, our study unveils a mechanistic role of the common variant rs2279590 that can affect a variety of aging disorders by regulating the expression of a specific set of genes.

Alleles

Alzheimer Disease - genetics

Alzheimer Disease - metabolism

Clusterin - biosynthesis

Clusterin - genetics

Enhancer Elements, Genetic

Epoxide Hydrolases - biosynthesis

Epoxide Hydrolases - genetics

Exfoliation Syndrome - genetics

Exfoliation Syndrome - metabolism

Focal Adhesion Kinase 2 - biosynthesis

Focal Adhesion Kinase 2 - genetics

Gene Frequency

Genetic Predisposition to Disease

Genetic Variation

Genotype

HEK293 Cells

Humans

Polymorphism, Single Nucleotide

Quantitative Trait Loci

Risk Factors

Details

Title: Subtitle: Pseudoexfoliation and Alzheimer's associated CLU risk variant, rs2279590, lies within an enhancer element and regulates CLU, EPHX2 and PTK2B gene expression
Creators: Biswajit Padhy - National Institute of Science Education and Research
Bushra Hayat - National Institute of Science Education and Research
Gargi Gouranga Nanda - National Institute of Science Education and Research
Pranjya Paramita Mohanty - Central Rice Research Institute
Debasmita Pankaj Alone - National Institute of Science Education and Research
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.26(22), pp.4519-4529
DOI: 10.1093/hmg/ddx329
PMID: 28973302
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Language: English
Date published: 11/15/2017
Academic Unit: Internal Medicine
Record Identifier: 9985157527102771

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