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Aryl Hydrocarbon Receptor-Mediated Regulation of Gene Expression during Cardiomyocyte Differentiation

Wang, Qin
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439307738

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Toxicology (Environmental Health).
The focus of this dissertation is on the identification of novel cardiac specific genes regulated by the aryl hydrocarbon receptor (AHR) and the mechanisms through which TCDD exposure induces cardiotoxicity, primarily regarding the dual roles of the receptor in both regulating cardiomyocyte differentiation and in mediating TCDD-caused cardiotoxicity. The AHR is a ligand-activated transcription factor that belongs to the basic-region-helix-loop-helix PER/ARNT/SIM (bHLH-PAS) super¬family of transcription factors. AHR has a wide range of ligands with the prototypical ligand being the persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Exposure to TCDD causes toxicity in multiple organs and organisms including the heart that is primarily mediated through AHR. The binding of TCDD to AHR leads to the translocation of the receptor from the cytosol to the nucleus where the receptor heterodimerizes with Aryl Hydrocarbon Receptor Translocator (ARNT) and consequently binds as a heterodimer to DNA, resulting the regulation of expression for hundreds of downstream genes. A battery of genes that have been extensively studied function in the metabolism of xenobiotics, i.e. cytochrome P450, family1 (Cyp1). Beyond the role in xenobiotic metabolism, the Ah receptor has an important role in basic physiologic processes such as cardiovascular development. The goal of this dissertation is to characterize the developmental role of the receptor as well as the consequences of developmental exposure to TCDD during cardiomyocyte differentiation. Chapter I gives a brief background on the chemical properties and toxicology of TCDD with a focus on the cardiotoxicity. The structure and molecular action of AHR as well as its role in cardiovascular development and homeostasis are described. In chapter II, we used next generation sequencing to analyze temporal trajectories of TCDD-dependent global gene expression in differentiating cells expressing the Ah receptor. We found hundreds of genes deregulated by AHR/TCDD axis, including those that regulate multiple signaling pathways involved in cardiac and neural morphogenesis and differentiation. The deregulated genes also include dozens of genes encoding homeobox transcription factors and Polycomb and trithorax group proteins, which are essential regulators of cardiomyogenesis. In chapter III, we investigated whether these cardiac specific genes regulated by AHR had a developmental window of sensitivity to TCDD exposure. Interestingly, we found that cardiomyocyte contractility was an AHR-dependent TCDD target solely during the early period of differentiation between days 0 and 3. Within the critical time window, TCDD disrupted the concerted expression of genes involved in the TGFß/BMP2/4 and WNT signaling pathways, significantly suppressed the autocrine secretion of upstream regulators including BMP4, WNT3a and WNT5a, and elevated the secretion of Activin A. TCDD treatment also causes mitochondrial dysfunction, including altered mitochondrial copy number, mitochondria ultrastructural stress, and damage. AHR activation by TCDD during early ES cell differentiation appears to disrupt the expression of signals critical to the ontogeny of cardiac mesoderm and causes the loss of contractility in the resulting cardiomyocyte lineage. The results presented throughout this work show the AHR functions related both to normal cardiomyocyte development and cardiac toxicological endpoints, and illustrate the ability of this important transcription factor to regulate the expression of a large number of genes in the context of cardiomyocyte differentiation.
Alvaro Puga, Ph.D. (Committee Chair)
Michael Borchers, Ph.D. (Committee Member)
Susan Kasper, Ph.D. (Committee Member)
Peter Stambrook, Ph.D. (Committee Member)
Ying Xia, Ph.D. (Committee Member)
199 p.
Toxicology
Aryl hydrocarbon receptor; Dioxin; Embryonic stem cells; Differentiation; Cardiomyogenesis; Gene expression

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Citations

  • Wang, Q. (2015). Aryl Hydrocarbon Receptor-Mediated Regulation of Gene Expression during Cardiomyocyte Differentiation [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439307738

    APA Style (7th edition)

  • Wang, Qin. Aryl Hydrocarbon Receptor-Mediated Regulation of Gene Expression during Cardiomyocyte Differentiation. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439307738.

    MLA Style (8th edition)

  • Wang, Qin. "Aryl Hydrocarbon Receptor-Mediated Regulation of Gene Expression during Cardiomyocyte Differentiation." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439307738

    Chicago Manual of Style (17th edition)

ucin1439307738
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This open access ETD is published by University of Cincinnati and OhioLINK.