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. 2017 Aug 16;14(8):921.
doi: 10.3390/ijerph14080921.

Association Between Promoter Methylation of Gene ERCC3 and Benzene Hematotoxicity

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Free PMC article

Association Between Promoter Methylation of Gene ERCC3 and Benzene Hematotoxicity

Min Zheng et al. Int J Environ Res Public Health. .
Free PMC article

Abstract

Benzene is a primary industrial chemical and a ubiquitous environmental pollutant. ERCC3 is a key player in nucleotide excision repair. Recent studies suggested that site-specific methylation is a possible mechanism of the transcriptional dysregulation by blocking transcription factors binding. We previously found that the average promoter methylation level of ERCC3 was increased in benzene-exposed workers. In order to test whether specific CpG sites of ERCC3 play an important role in benzene-induced epigenetic changes and whether the specific methylation patterns are associated with benzene hematotoxicity, we analyzed the promoter methylation levels of individual CpG sites, transcription factor binding motif and the correlation between aberrant CpG methylation and hematotoxicity in 76 benzene-exposed workers and 24 unexposed controls in China. Out of all the CpGs analyzed, two CpG units located 43 bp upstream and 99 bp downstream of the transcription start site of ERCC3 (CpG 2-4 and CpG 17-18, respectively), showed the most pronounced increase in methylation levels in benzene-exposed workers, compared with unexposed controls (Mean ± SD: 5.86 ± 2.77% vs. 4.92 ± 1.53%, p = 0.032; 8.45 ± 4.09% vs. 6.79 ± 2.50%, p = 0.024, respectively). Using the JASPAR CORE Database, we found that CpG 2-4 and CpG 17-18 were bound by three putative transcription factors (TFAP2A, E2F4 and MZF1). Furthermore, the methylation levels for CpG 2-4 were correlated negatively with the percentage of neutrophils (β = -0.676, p = 0.005) in benzene-exposed workers. This study demonstrates that CpG-specific DNA methylation in the ERCC3 promoter region may be involved in benzene-induced epigenetic modification and it may contribute to benzene-induced hematotoxicity.

Keywords: ERCC3; benzene; hematotoxicity; methylation; occupational exposure.

Conflict of interest statement

The authors declare no conflict of interest. The founding sponsors hadn’t involved in the design of the study; in the sample collection, data analyses and interpretation; in the writing of the manuscript, and in the decision to publish the study results.

Figures

Figure 1
Figure 1
(A) The CpG dinucleotides contained TFBSs in the investigated sequence for methylation of ERCC3 promoterregion. (B) The TFBSs and enrichment of H3K4me3 and H3K27ac modification in ERCC3 promoter region in human embryonic stem cells (hESC) (Green area) and in K562 cells (Blue area). Red triangle indicated CpG unit. * TFBSs by JASPAR CORE Database (http://jaspar.genereg.net/). ** HMR Conserved TFBSs by Transfac Matrix Database (v.7.0) (https://genome.ucsc.edu/). TFAP2A: transcription factors activating enhancer binding protein 2 alpha, MZF1: myeloid zinc finger-1, TSS: transcriptional start site, TFBSs: transcription factor binding sites.

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