Decreased topoisomerase IIalpha expression and altered histone and regulatory factors of topoisomerase IIalpha promoter in patients with chronic benzene poisoning.

摘要

Topoisomerase IIalpha (Topo IIalpha) has been implicated in the benzene-induced hemotoxicity in vitro. This study was to examine the effect of in vivo chronic benzene exposure on Topo IIalpha in human bone marrow mononuclear cells, and to further explore the mechanism underlying decreased Topo IIalpha expression in patients with chronic benzene exposure. Topo IIalpha activity, expression, and mRNA level assessed by DNA cleavage/relaxation assay, Western blot, and reverse transcriptase-PCR, decreased in patients with benzene exposure. These changes were accompanied by reduced histone H4 and H3 acetylation and H3K4 methylation, and increased H3K9 methylation in the Topo IIalpha promoter, which were evaluated by chromatin immunoprecipitation (ChIP) assay. In addition, there were alterations in mRNA levels of Topo IIalpha promoter regulatory factors such as SP1, ATF-2, SP3, NF-YA, NF-M, P53, C-MYB, C-JUN, and ICBP90. Our results demonstrate that Topo IIalpha expression was reduced in patients with chronic benzene exposure, which was accompanied by alterations in histone acetylation and methylation and regulatory factor mRNA levels of Topo IIalpha promoter.