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Toxicol Appl Pharmacol. 2018 Oct 15;357:70-79. doi: 10.1016/j.taap.2018.08.011. Epub 2018 Aug 18.

Sodium arsenite exposure inhibits histone acetyltransferase p300 for attenuating H3K27ac at enhancers in mouse embryonic fibroblast cells.

Author information

1
Laboratory of Human Environmental Epigenome, Department of Environmental Health & Engineering, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe St., Baltimore, MD 21205, USA.
2
Laboratory of Human Environmental Epigenome, Department of Environmental Health & Engineering, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe St., Baltimore, MD 21205, USA; Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, 368 Youyi Avenue, Wuchang District, Wuhan, Hubei Province 430062, China.
3
Laboratory of Human Environmental Epigenome, Department of Environmental Health & Engineering, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe St., Baltimore, MD 21205, USA; Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China.
4
GENEWIZ Suzhou, 218 Xinghu Road, Suzhou Industrial Park, Suzhou 215123, China. Electronic address: yankai.jia@genewiz.com.
5
Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, 368 Youyi Avenue, Wuchang District, Wuhan, Hubei Province 430062, China. Electronic address: haimou@hubu.edu.cn.
6
Laboratory of Human Environmental Epigenome, Department of Environmental Health & Engineering, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe St., Baltimore, MD 21205, USA; Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, 368 Youyi Avenue, Wuchang District, Wuhan, Hubei Province 430062, China; Fengxian Central Hospital, 9588 Nanfeng Hwy, Fengxian District, Shanghai 201406, China. Electronic address: zwang47@jhu.edu.

Abstract

Both epidemiological investigations and animal studies have linked arsenic-contaminated water to cancers, including skin, liver and lung cancers. Besides genotoxicity, arsenic exposure-related pathogenesis of disease is widely considered through epigenetic mechanisms; however, the underlying mechanism remains to be determined. Herein we explore the initial epigenetic changes via acute sodium arsenite (As) exposures of mouse embryonic fibroblast (MEF) cells and histone H3K79 methyltransferase Dot1L knockout (Dot1L-/-) MEF cells. Our RNA-seq and Western blot data demonstrated that, in both cell lines, acute As exposure abolished histone acetyltransferase p300 at the RNA level and subsequent protein level. Consequently, p300-specific main target histone H3K27ac, a marker separating active from poised enhancers, decreased dramatically as validated by both Western blot and ChIP-qPCR/seq analyses. Concomitantly, H3K4me1 as another well-known marker for enhancers also showed significant decreases, suggesting an underappreciated crosstalk between H3K4me1 and H3K27ac involved in As exposure. Significantly, As exposure-reduced H3K27ac and H3K4me1 inhibited the expression of genes including EP300 itself and Kruppel Like Factor 4(Klf4) that both are tumor suppressor genes. Collectively, our investigations identified p300 as an internal bridging factor within cells to sense external environmental As exposure to alter chromatin, thereby changing gene transcription for disease pathogenesis.

KEYWORDS:

Cancers; Enhancers; H3K27ac; Histone acetyltransferase p300; Sodium arsenite

PMID:
30130555
PMCID:
PMC6526104
DOI:
10.1016/j.taap.2018.08.011
[Indexed for MEDLINE]
Free PMC Article

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