Epigenetic alteration of mismatch repair genes in the population chronically exposed to arsenic in West Bengal, India

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Abstract

Introduction

Arsenic exposure and its adverse health outcome, including the association with cancer risk are well established from several studies across the globe. The present study aims to analyze the epigenetic regulation of key mismatch repair (MMR) genes in the arsenic-exposed population.

Method

A case-control study was conducted involving two hundred twenty four (N=224) arsenic exposed [with skin lesion (WSL=110) and without skin lesion (WOSL=114)] and one hundred and two (N=102) unexposed individuals. The methylation status of key MMR genes i.e. MLH1, MSH2, and PMS2 were analyzed using methylation-specific PCR (MSP). The gene expression was studied by qRTPCR. The expression of H3K36me3, which was earlier reported to be an important regulator of MMR pathway, was assessed using ELISA.

Results

Arsenic-exposed individuals showed significant promoter hypermethylation (p < 0.0001) of MLH1 and MSH2 compared to those unexposed with consequent down-regulation in their gene expression [MLH1 (p=0.001) and MSH2 (p<0.05)]. However, no significant association was found in expression and methylation of PMS2 with arsenic exposure. We found significant down-regulation of H3K36me3 in the arsenic-exposed group, most significantly in the WSL group (p<0.0001). The expression of SETD2, the methyltransferase of an H3K36me3 moiety was found to be unaltered in arsenic exposure, suggesting the involvement of other regulatory factors yet to be identified.

Discussion

In summary, the epigenetic repression of DNA damage repair genes due to promoter hypermethylation of MLH1 and MSH2 and inefficient recruitment of MMR complex at the site of DNA damage owing to the reduced level of H3K36me3 impairs the mismatch repair pathway that might render the arsenic-exposed individuals more susceptible towards DNA damage and associated cancer risk.

Graphical abstract

A case-control study was designed to analyze the methylation status of key MMR genes i.e. MLH1, MSH2, and PMS2 using methylation-specific PCR (MSP) and their gene expression alterations by qRTPCR in arsenic exposed population. The expression of H3K36me3, an important regulator of MMR pathway, was found to be down regulated by ELISA based assay. This might hinder the efficient recruitment of MMR proteins at the site of DNA mismatches. The promoter of both MLH1, MSH2 was found to be hypermethylated with consequent down regulated expression pattern. Theses altogether indicate compromised MMR pathway in arsenic exposed population.

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