Promoter hypermethylation in CSF3R induces peripheral neutrophil reduction in benzene‐exposure poisoning

Abstract

Benzene is a global pollutant and has been established to cause leukemia. To better understand the role of DNA methylation in benzene toxicity, peripheral blood mononuclear cells were collected from six benzene-poisoning patients and six matched controls for genome-wide DNA methylation screening by Illumina Infinium Methylation 450 BeadChip. The Gene Chip Human Gene 2.0 ST Array (Affymetrix) was used to analyze global mRNA expression. Compared with the corresponding sites of controls, 442 sites in patients were hypermethylated, corresponding to 253 genes, and 237 sites were hypomethylated, corresponding to 130 genes. The promoter methylation and mRNA expression of CSF3R, CREB5, and F2R were selected for verification by bisulfite sequencing and real-time PCR in a larger data set with 21 cases and 23 controls. The results indicated that promoter methylation of CSF3R (p = .005) and F2R (p = .015) was significantly higher in cases than in controls. Correlation analysis showed that the promoter methylation of CSF3R (p < .001) and F2R (p < .001) was highly correlated with its mRNA expression. In the poisoning cases, neutrophil percentage was significantly different among the high, middle, and low CSF3Rmethylation groups (p = .002). In particular, the neutrophil percentage in the high CSF3R-methylation group (48.10 ± 9.63%) was significantly lower than that in the low CSF3R-methylation group (59.30 ± 6.26%) (p = .012). The correlation coefficient between promoter methylation in CSF3R and the neutrophil percentage was −0.445 (p = .020) in cases and − 0.398 (p = .060) in controls. These results imply that hypermethylation occurs in the CSF3R promoter due to benzene exposure and is significantly associated with a reduction in neutrophils.

Toxicomethylomics revisited: A state-of-the-science review about DNA methylation modifications in blood cells from workers exposed to toxic agents

“…Wang et al ( 16 ) studied mitochondrial DNA methylation, specifically at the Mitochondrially Encoded Cytochrome c Oxidase I ( MT-COI ) gene, and reported two interesting results: mitochondrial methylation was lower in the exposed group; and methylation of MT-COI was correlated with white blood cell count and also with platelet levels. Epigenome-wide analysis was performed on a large scale for the first time by Ren et al ( 17 ), using the Infinium 450K methylation microarray. They reported 442 sites in benzene-exposed participants were hypermethylated, corresponding to 253 genes, and 237 sites were hypomethylated, corresponding to 130 genes.…”

Identification of novel immune-related biomarker and therapeutic drugs in Parkinson disease via integrated bioinformatics analysis

“…These key genes had potential regulatory effects on granulocyte proliferation and differentiation, immune response, pro-inflammatory activity and immune checkpoint factors. [13,14] Previous studies have identified some biomarkers of PD, but have no immune-related biomarkers. Songyun Zhao et al [15] identified 3 cuprotosis-related genes ATP7A, SLC31A1, and DBT associated with immune cells or immune function in PD and more accurate for the diagnosis of Parkinson disease course.…”

Expression characteristics of long noncoding RNA and messenger RNA in human traumatic brain injury

“…CSF3R is a type 1 cytokine receptor that binds granulocyte CSF, a cytokine vital for granulocyte proliferation and differentiation [29]. Acquired nonsense and frameshift truncation variants in the cytoplasmic domain and activating missense variants in the membrane-proximal region of CSF3R are found in a majority of cases of chronic neutrophilic leukemia, atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, and de-novo acute myeloid leukemia [30].…”