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

Yan Zhu, Yanqiang Li, Dan Lou, Yang Gao, Jing Yu, Dehui Kong, Qiang Zhang, Yankai Jia, Haimou Zhang, Zhibin Wang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)70-79
Number of pages10
JournalToxicology and Applied Pharmacology
Volume357
DOIs
StatePublished - Oct 15 2018

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Histone Acetyltransferases
Fibroblasts
Cells
Genes
Arsenic
Skin Neoplasms
Epigenomics
Lung Neoplasms
Western Blotting
RNA
Environmental Exposure
Transcription
Liver Neoplasms
Crosstalk
Tumor Suppressor Genes
Knockout Mice
Liver
Histones
Chromatin
Tumors

Keywords

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

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Sodium arsenite exposure inhibits histone acetyltransferase p300 for attenuating H3K27ac at enhancers in mouse embryonic fibroblast cells. / Zhu, Yan; Li, Yanqiang; Lou, Dan; Gao, Yang; Yu, Jing; Kong, Dehui; Zhang, Qiang; Jia, Yankai; Zhang, Haimou; Wang, Zhibin.

In: Toxicology and Applied Pharmacology, Vol. 357, 15.10.2018, p. 70-79.

Research output: Contribution to journalArticle

Zhu, Yan ; Li, Yanqiang ; Lou, Dan ; Gao, Yang ; Yu, Jing ; Kong, Dehui ; Zhang, Qiang ; Jia, Yankai ; Zhang, Haimou ; Wang, Zhibin. / Sodium arsenite exposure inhibits histone acetyltransferase p300 for attenuating H3K27ac at enhancers in mouse embryonic fibroblast cells. In: Toxicology and Applied Pharmacology. 2018 ; Vol. 357. pp. 70-79.
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AU - Lou, Dan

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AU - Yu, Jing

AU - Kong, Dehui

AU - Zhang, Qiang

AU - Jia, Yankai

AU - Zhang, Haimou

AU - Wang, Zhibin

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AB - 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.

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