Aberrant hypomethylated STAT3 was identified as a biomarker of chronic benzene poisoning through integrating DNA methylation and mRNA expression data

Abstract

Chronic occupational benzene exposure is associated with an increased risk of hematological malignancies such as aplastic anemia and leukemia. The new biomarker and action mechanisms of chronic benzene poisoning are still required to be explored. Aberrant DNA methylation, which may lead to genomic instability and the altered gene expression, is frequently observed in hematological cancers. To gain an insight into the new biomarkers and molecular mechanisms of chronic benzene poisoning, DNA methylation profiles and mRNA expression pattern from the peripheral blood mononuclear cells of four chronic benzene poisoning patients and four health controls that matched age and gender without benzene exposure were performed using the high resolution Infinium 450K methylation array and Gene Chip Human Gene 2.0ST Arrays, respectively. By integrating DNA methylation and mRNA expression data, we identified 3 hypermethylated genes showing concurrent down-regulation (PRKG1, PARD3, EPHA8) and 2 hypomethylated genes showing increased expression (STAT3, IFNGR1). Signal net analysis of differential methylation genes associated with chronic benzene poisoning showed that two key hypomethylated STAT3 and hypermethylated GNAI1 were identified. Further GO analysis and pathway analysis indicated that hypomethylated STAT3 played central roles through regulation of transcription, DNA-dependent, positive regulation of transcription from RNA polymerase II promoter, JAK-STAT cascade and adipocytokine signaling pathway, Acute myeloid leukemia, and JAK-STAT signaling pathway. In conclusion, the aberrant hypomethylated STAT3 might be a potential biomarker of chronic benzene poisoning.

Keywords: Biomarkers; Chronic benzene poisoning; DNA methylation; STAT3.