Oxidative stress is a common effect of a number of environmental stressors. Hypoxia can also produce O2*- (superoxide) when the mitochondrial electron transport has been disrupted by lack of oxygen. Recent work related to 2-oxoglutarate (2-OG) dependent dioxygenases makes it clear that there are additional effects of hypoxia and oxidative stress beyond those mediated through HIFs. The 2-oxoglutarate dependent dioxygenases, which regulate epigenetic parameters, include oxidative histone demethylases and TET proteins, the 5-methylcytosine (5mC) hydroxylases. These enzymes require O2 to function and are also affected by oxidative stress. We believe that the inability to hydroxylate 5mC in DNA and demethylate a number of histone lysines due to the inactivation of 2-oxoglutarate dependent dioxygenases, is likely to have major effects on a cell's epigenetic program resulting in inherited aberrations in gene expression. We hypothesize that oxidative stress (and hypoxia) induced by a variety of environmental insults is upstream of persistent and inherited epigenetic changes that can lead to diseases such as cancer, via their ability to transiently inhibit the activity of the 2-oxoglutarate dependent histone demethylases and TET proteins. We will investigate the effect of various chemical agents that produce oxidative stress or hypoxia signaling on the epigenetic program by identifying which of the above dioxygenases is inactivated by oxidative stress and hypoxia. We hypothesize that measuring the mRNA and protein levels of the oxidative demethylases, which are upregulated when their enzymatic activities are inhibited, will identify the demethylases that are affected by oxidative stress or hypoxia. In addition, global levels of histone modifications and DNA methylation and hydroxymethylation will be assessed to confirm the identity of oxidative demethylases that are inhibited. Specificity to oxidative stress will be examined using antioxidants such as reduced ascorbate or vitamin E. We will map on a genome-wide scale epigenetic modifications that are affected by the inhibition of oxidative demethylases using ChIP-Seq. We will also study which histone modification marks, 5mC, 5-hydroxymethylcytosine (5hmC) and gene expression changes persist following removal of the oxidative stress in relevant gene promoters and also selected modifications will be mapped on a genome wide scale using ChIP-Seq. To investigate the effects of persistent chromatin alterations due to the inactivation of oxidative demethylases chromatin accessibility will be assessed on a genome-wide scale using FAIRE-Seq in the absence and presence of oxidative stress/hypoxia with a focus on understanding the persistence of these sites after oxidative stress is terminated for a number of cell generations. Decreases in binding of critical transcription factors due to reduced chromatin accessibility will be predicted by computational approaches and confirmed by genome-wide mapping of candidate factors in the absence and presence of oxidative stress/hypoxia, with a focus on understanding which changes persist after the stress has ceased.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES023174-01
Application #
8582413
Study Section
Special Emphasis Panel (ZES1-LWJ-D (TG))
Program Officer
Tyson, Frederick L
Project Start
2013-08-20
Project End
2017-05-31
Budget Start
2013-08-20
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$539,213
Indirect Cost
$219,624
Name
New York University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Jagannathan, Lakshmanan; Jose, Cynthia C; Tanwar, Vinay Singh et al. (2017) Identification of a unique gene expression signature in mercury and 2,3,7,8-tetrachlorodibenzo-p-dioxin co-exposed cells. Toxicol Res (Camb) 6:312-323
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
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
Barski, Artem; Cuddapah, Suresh; Kartashov, Andrey V et al. (2017) Rapid Recall Ability of Memory T cells is Encoded in their Epigenome. Sci Rep 7:39785
Jagannathan, Lakshmanan; Cuddapah, Suresh; Costa, Max (2016) Oxidative stress under ambient and physiological oxygen tension in tissue culture. Curr Pharmacol Rep 2:64-72
Cartularo, Laura; Kluz, Thomas; Cohen, Lisa et al. (2016) Molecular Mechanisms of Malignant Transformation by Low Dose Cadmium in Normal Human Bronchial Epithelial Cells. PLoS One 11:e0155002
Wu, Feng; Jordan, Ashley; Kluz, Thomas et al. (2016) SATB2 expression increased anchorage-independent growth and cell migration in human bronchial epithelial cells. Toxicol Appl Pharmacol 293:30-6
Jagannathan, Lakshmanan; Jose, Cynthia C; Arita, Adriana et al. (2016) Nuclear Factor ?B1/RelA Mediates Inflammation in Human Lung Epithelial Cells at Atmospheric Oxygen Levels. J Cell Physiol 231:1611-20
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
Muñoz, Alexandra; Chervona, Yana; Hall, Megan et al. (2015) Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water. Toxicol Appl Pharmacol 284:330-8

Showing the most recent 10 out of 27 publications