TY - JOUR
T1 - Sodium arsenite exposure inhibits histone acetyltransferase p300 for attenuating H3K27ac at enhancers in mouse embryonic fibroblast cells
AU - Zhu, Yan
AU - Li, Yanqiang
AU - Lou, Dan
AU - Gao, Yang
AU - Yu, Jing
AU - Kong, Dehui
AU - Zhang, Qiang
AU - Jia, Yankai
AU - Zhang, Haimou
AU - Wang, Zhibin
N1 - Funding Information:
The laboratory of Z.W was supported by National Institutes of Health , United States (R01ES25761, U01ES026721 opportunity fund, and R21ES028351) and Johns Hopkins Catalyst Award . Q.Z thanks China Scholarship Council , China and the National Natural Science Foundation of China ( 81302390 ) for support. This work was also made possible by the ChuTian Professorship from Hubei University, China and support from GENEWIZ Suzhou. Lastly, extensive bioinformatic analyses were possible only with computational resources (and/or scientific computing services) at the Maryland Advanced Research Computing Center (MARCC). We are therefore greatly indebted to the support from MARCC.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/10/15
Y1 - 2018/10/15
N2 - 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.
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.
KW - Cancers
KW - Enhancers
KW - H3K27ac
KW - Histone acetyltransferase p300
KW - Sodium arsenite
UR - http://www.scopus.com/inward/record.url?scp=85052971254&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052971254&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2018.08.011
DO - 10.1016/j.taap.2018.08.011
M3 - Article
C2 - 30130555
AN - SCOPUS:85052971254
SN - 0041-008X
VL - 357
SP - 70
EP - 79
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
ER -