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Cr(VI) Disrupts Chromatin Architecture

VonHandorf, Andrew P
http://orcid.org/0000-0003-2495-2324
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595243461574043

Abstract Details

2020, PhD, University of Cincinnati, Medicine: Toxicology (Environmental Health).
The focus of this dissertation is the characterization of Cr(VI)'s disruption of chromatin architecture and its effects on the regulation of transcription, particularly through disruption of the CCCTC-binding factor's (CTCF) ability to recognize its cognate binding sites, and how this may promote tumor initiation and progression. The class of compounds containing Cr(VI), commonly known as chromates, are well-established respiratory carcinogens in occupational industries that include stainless steel production and welding, electroplating, and pigment production, among others. However, heavy use of these compounds in these processes results in environmental contamination, with global populations potentially exposed over the course of a lifetime to low levels of Cr(VI), primarily through ingestion in the form of drinking water. While several studies provide evidence for the adverse health outcomes associated with exposure, the mechanisms that induce these endpoints are not well understood. Cr(VI) promotes the generation of reactive oxygen species as well as the formation of Cr-DNA and ligand-Cr-DNA adducts, resulting in increased DNA damage, silencing of tumor suppressor genes, and genomic instability. Together with epidemiological and animal studies, this evidence suggests that Cr(VI) has carcinogenic properties regardless of exposure route and highlights the need to better understand how long-term exposure to low levels of chromates affects the risk of developing cancer. By studying the molecular mechanisms of Cr(VI) that promote carcinogenesis, this work contributes to the body of evidence used to inform public health decisions and risk mitigation. Chapter 1 provides a summary of the current understanding of Cr(VI), its relevance to Public Health, and the mechanisms that contribute to its carcinogenic properties. Chapter 2 characterizes the disruption of chromatin organization that occurs in vitro following treatment with Cr(VI) and how that affects CTCF's access to its cognate binding sites in promoter regions of genes using multiple next-generation sequencing techniques. Chapter 3 further investigates the enrichment of CTCF motifs in differentially-accessible chromatin and its association with the regulation of transcription using Chromatin Immunoprecipitation couple with next-generation sequencing to assess changes in binding affinity of CTCF and the impact on localized histone modification signals. Chapter 4 discusses the findings of the previous chapters and provides a summary of the conclusions as well as future directions. Overall, the research presented in this work illustrate that Cr(VI) disrupts chromatin organization through changes in chromatin accessibility, particularly around CTCF binding sites, and that these architectural fluctuations potentially promote dysregulation of the transcriptome.
Alvaro Puga, Ph.D. (Committee Chair)
Susan Kasper, Ph.D. (Committee Member)
Liang Niu, Ph.D. (Committee Member)
Peter Stambrook, Ph.D. (Committee Member)
Ying Xia, Ph.D. (Committee Member)
177 p.
Toxicology
Hexavalent Chromium; Epigenetics; Chromatin Accessibility; Metals Carcinogenesis; Transcription Regulation; Chromatin Architecture

Recommended Citations

Citations

  • VonHandorf, A. P. (2020). Cr(VI) Disrupts Chromatin Architecture [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595243461574043

    APA Style (7th edition)

  • VonHandorf, Andrew. Cr(VI) Disrupts Chromatin Architecture. 2020. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595243461574043.

    MLA Style (8th edition)

  • VonHandorf, Andrew. "Cr(VI) Disrupts Chromatin Architecture." Doctoral dissertation, University of Cincinnati, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595243461574043

    Chicago Manual of Style (17th edition)

ucin1595243461574043
101
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This open access ETD is published by University of Cincinnati and OhioLINK.
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