Analysis of arsenic-induced gene expression in peripheral blood mononuclear cells (PMBCs) demonstrated a profound increase in the histone cluster gene expression: of the 50 most upregulated arsenic induced genes, 22 were replication-dependent canonical histone genes. The canonical histone genes are the only genes in multicellular organisms whose messenger RNA (mRNA) does not terminate at the 3' end with a poly (A) tail. Intriguingly, arsenic exposure induced polyadenylation of the canonical histone mRNA. This was accompanied by an increase in histone protein expression and a depletion of stem loop binding protein (SLBP). SLBP is a key factor in processing replication-dependent canonical histones pre-mRNA. It has been shown that depletion of SLBP results in histone mRNA misprocessing, generating canonical histone mRNAs with poly (A) tails. The mRNA coding for SLBP was also decreased in various cell types following arsenic exposure, whereas none of the other factors needed to process canonical histone mRNA were altered, suggesting that the reduction of SLBP expression is the major cause of arsenic-induced polyadenylation of canonical histone mRNA and the increase in histone protein expression. The addition of the poly (A) tail to the canonical histone mRNA will increase the mRNA stability, allowing for the polyadenylated histones to be present not only in the S phase, but in other phases of the cell cycle as well. In fact, after arsenic treatment canonical histone H3 with a poly (A) tail was 3- fod higher during mitosis compared to untreated cells. These effects of arsenic could be very disruptive to nucleosome assembly and transcription and may be involved in mediating arsenic carcinogenesis. Our research has focused on metals, epigenetics and cancer, with an emphasis on metal induced changes in histone modifications and how they impact transcription. However, we have never observed any metal that causes such a profound effect on the induction of histone genes and at such low concentrations (0.1-0.5 M). In this project, we will investigate how arsenic exposure results in the loss of SLBP, focusing on the activation of a phosphorylation dependent degradation process, and epigenetic changes in the SLBP promoter. We will also determine the consequences of arsenic-induced acquisition of poly (A) containing canonical histone H3 in terms of nucleosome assembly, transcription, cell cycle, and genomic stability. In addition, we will examine the impact of depletion and re-expression of SLBP in the absence and presence of arsenic exposure on cell transformation. Finally, we will study whether arsenic exposure in mice induces a loss of SLBP, increases poly (A) containing canonical histone mRNA and histone protein in vivo.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (SIEE)
Program Officer
Tyson, Frederick L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
Public Health & Prev Medicine
Schools of Medicine
New York
United States
Zip Code
Chen, Danqi; Fang, Lei; Li, Hongjie et al. (2018) The effects of acetaldehyde exposure on histone modifications and chromatin structure in human lung bronchial epithelial cells. Environ Mol Mutagen 59:375-385
Chen, Qiao Yi; Costa, Max (2018) PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis. Mol Pharmacol 94:784-792
Chen, Danqi; Fang, Lei; Mei, Shenglin et al. (2018) Erratum: ""Regulation of Chromatin Assembly and Cell Transformation by Formaldehyde Exposure in Human Cells"". Environ Health Perspect 126:019001
Chen, Danqi; Fang, Lei; Mei, Shenglin et al. (2017) Regulation of Chromatin Assembly and Cell Transformation by Formaldehyde Exposure in Human Cells. Environ Health Perspect 125:097019
Jordan, Ashley; Zhang, Xiaoru; Li, Jinquan et al. (2017) Nickel and cadmium-induced SLBP depletion: A potential pathway to metal mediated cellular transformation. PLoS One 12:e0173624
Abu-Elmagd, Muhammad; Alghamdi, Mansour A; Shamy, Magdy et al. (2017) Evaluation of the Effects of Airborne Particulate Matter on Bone Marrow-Mesenchymal Stem Cells (BM-MSCs): Cellular, Molecular and Systems Biological Approaches. Int J Environ Res Public Health 14:
Laulicht-Glick, Freda; Wu, Feng; Zhang, Xiaoru et al. (2017) Tungsten exposure causes a selective loss of histone demethylase protein. Mol Carcinog 56:1778-1788
Howe, Caitlin G; Liu, Xinhua; Hall, Megan N et al. (2017) Sex-Specific Associations between One-Carbon Metabolism Indices and Posttranslational Histone Modifications in Arsenic-Exposed Bangladeshi Adults. Cancer Epidemiol Biomarkers Prev 26:261-269
Chen, Danqi; Kluz, Thomas; Fang, Lei et al. (2016) Hexavalent Chromium (Cr(VI)) Down-Regulates Acetylation of Histone H4 at Lysine 16 through Induction of Stressor Protein Nupr1. PLoS One 11:e0157317
Fang, Lei; Chen, Danqi; Yu, Clinton et al. (2016) Mechanisms Underlying Acrolein-Mediated Inhibition of Chromatin Assembly. Mol Cell Biol 36:2995-3008