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Cite This: Chem. Res. Toxicol. XXXX, XXX, XXX−XXX
Chromatin Modifications in Toxicology James J. Galligan* Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States
Chem. Res. Toxicol. Downloaded from pubs.acs.org by 185.46.84.218 on 12/19/18. For personal use only.
ABSTRACT: Histone modifications regulate chromatin structure and function. Primary and secondary metabolites stemming from environmental and chemical exposures may play a critical role in the underlying epigenomic state of a cell through covalent histone modifications. Future investigations should be focused on characterizing the “Histone Code” when performing toxicogenomic analyses.
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of acetylation and disrupted chromatin assembly.2 This demonstrates that cigarette smoke is capable of disrupting the underlying epigenetic signature of a cell via direct modification by acrolein. Akin to acrolein, the pro-inflammatory lipid aldehyde, 4-oxo-2-nonenal, has also been shown to modify histones, disrupting nucleosome structure.3 Due to the complexity and dynamic nature of chromatin and histone PTMs, investigations into these modifications remain a daunting task; however, advances in chemical biology have provided the tools to investigate these modifications in detail by allowing for the selective enrichment of modified histones. By appending an alkyne tag to a molecule of interest, click chemistry can be employed to precisely measure site-specific PTMs derived from the probe. Further, this selective enrichment can be utilized to conduct a full proteomic survey of histone PTMs, elucidating cross-talk for these novel and uncharacterized modifications. These chemical biology approaches coupled with high-throughput sequencing will allow toxicologists to integrate epigenomic and epiproteomic investigations into standard toxicogenomic analyses. The laboratory of Yingming Zhao has identified and characterized numerous histone PTMs resulting from cell metabolism and chemical exposures. Using high mass accuracy mass spectrometry and bioinformatic approaches, they have developed and employed PTMap, a sequence alignment software capable of accurate identification of protein PTMs.4 This approach was recently utilized to identify 22 sites of Lys benzoylation on histones.5 Derived from sodium benzoate, this widely used chemical preservative has been characterized by the FDA as “generally regarded as safe”. This work, however, demonstrates the ability of benzoate to undergo conjugation to CoA and directly modify histones, resulting in altered gene transcription associated with glycerophospholipid metabolism, ovarian steroidogenesis, and phospholipase D signaling. Although sodium benzoate is not overtly toxic, these studies highlight potentially long-lasting epigenetic alterations resulting from direct modification of histones by a single exposure. It is important to consider similar mechanisms with other widely utilized carboxylic acid-containing preservatives such as salicylic acid. A full characterization of the histone PTM landscape in cells and/or animals exposed to these toxicants
hromatin is made-up of the nearly 3 billion DNA bases in the human genome tightly wound around histone proteins. Histones undergo a plethora of post-translational modifications (PTMs) that regulate chromatin structure, DNA accessibility, and ultimately gene expression. PTMs are dynamically regulated by the activity of protein “writers” (addition), “readers”, and “erasers” (removal). This provides multiple levels of quality control to prevent the inheritance of detrimental gene expression. This underlying “epigenome” can be impacted following changes in cell metabolism, drug regimens, alterations in diet, and exposure to environmental chemicals. Although many factors impact chromatin structure and function, chromatin regulation is primarily achieved through three major processes: (1) modulation of writer, reader, and/or eraser activity; (2) alterations in DNA modifications; and (3) covalent modification of DNA and/or histones. A disruption in histone and/or DNA modifications can influence gene expression and have profound consequences on phenotypic responses. Histone PTMs mediate the relaxation of chromatin and open gene transcription (euchromatin) or compaction (heterochromatin) to prevent access to regions of the genome. Decades of research have highlighted the detrimental effects of chemical toxicants on DNA integrity, which may lead to mutagenesis, double-strand breaks, disrupted transcription, and altered cytosine methylation. Coinciding with these perturbations in DNA structure/function, precise changes in histone PTMs also take place. For example, heavy metal exposures have been shown to increase the acetylation of histone H3 at Lys 9.1 Methylation at H3 Lys 9 establishes epigenetic inheritance of heterochromatin assembly; thus, increased acetylation following exposure to arsenic can be directly linked to alterations in gene expression and epigenetic inheritance. Investigations into the effects of chemical toxicants on the epigenome are often focused on alterations in known histone PTMs (e.g., acetylation, methylation). Recently, the direct modification of histones and/or DNA by primary and secondary metabolites of chemical exposures is increasingly recognized as a mechanism by which long-term alterations in gene expression may occur. Histone adduction resulting from electrophilic metabolites has been shown to disrupt chromatin structure, basal histone PTMs, and gene expression. Acrolein, a constituent of cigarette smoke, modifies Lys residues on histones, resulting in a block © XXXX American Chemical Society
Special Issue: Epigenetics in Toxicology
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DOI: 10.1021/acs.chemrestox.8b00267 Chem. Res. Toxicol. XXXX, XXX, XXX−XXX
ToxWatch
Chemical Research in Toxicology
(4) Chen, Y., Chen, W., Cobb, M. H., and Zhao, Y. (2009) PTMap– a sequence alignment software for unrestricted, accurate, and fullspectrum identification of post-translational modification sites. Proc. Natl. Acad. Sci. U. S. A. 106, 761−766. (5) Huang, H., Zhang, D., Wang, Y., Perez-Neut, M., Han, Z., Zheng, Y. G., Hao, Q., and Zhao, Y. (2018) Lysine benzoylation is a histone mark regulated by SIRT2. Nat. Commun. 9, 3374.
may help explain why compounds are initially regarded as “safe” despite future investigations proving the contrary. By applying mass spectrometry with bioinformatic strategies, these types of investigations are now possible and should become a routine analysis in the chemical toxicologist’s toolbox. The NIEHS has increased the availability of funding to determine the effects of exposures to heavy metals, air pollutants, endocrine disruptors, pesticides, and other contaminants on the epigenome. The goal of these programs is to elucidate the mechanisms by which exposures may impact the epigenome and how this information is passed to future generations. By integrating chemical biology and proteomic analyses into toxicological evaluations, researchers now have the capability to better understand the consequences of exposure-related events on heritability and long-lasting gene expression changes.
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AUTHOR INFORMATION
Corresponding Author
*Phone: 520-621-6015. E-mail:
[email protected]. edu. ORCID
James J. Galligan: 0000-0002-5612-0680 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. The author declares no competing financial interest.
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REFERENCES
(1) Ren, X., McHale, C. M., Skibola, C. F., Smith, A. H., Smith, M. T., and Zhang, L. (2011) An emerging role for epigenetic dysregulation in arsenic toxicity and carcinogenesis. Environ. Health Perspect. 119, 11−19. (2) Chen, D., Fang, L., Li, H., Tang, M. S., and Jin, C. (2013) Cigarette smoke component acrolein modulates chromatin assembly by inhibiting histone acetylation. J. Biol. Chem. 288, 21678−21687. (3) Galligan, J. J., Rose, K. L., Beavers, W. N., Hill, S., Tallman, K. A., Tansey, W. P., and Marnett, L. J. (2014) Stable histone adduction by 4-oxo-2-nonenal: a potential link between oxidative stress and epigenetics. J. Am. Chem. Soc. 136, 11864−11866. B
DOI: 10.1021/acs.chemrestox.8b00267 Chem. Res. Toxicol. XXXX, XXX, XXX−XXX
