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Balow SA ETD 4.4.14.pdf (2.51 MB)

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Investigation of CHD7 Function in Developmental Models of CHARGE Syndrome

Balow, Stephanie Ann
http://rave.ohiolink.edu/etdc/view?acc_num=case1396625345

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Genetics.
Epigenetic regulation of the genome is essential for regulating gene expression to ensure proper tissue differentiation and patterning during embryonic development. The importance of epigenetic regulation is best highlighted by the large number of diseases that arises from its misregulation. One particular epigenetic regulator that signifies this importance is the chromatin remodeling protein, CHD7. Changes in CHD7 expression during development results in a congenital disorder known as CHARGE syndrome comprising a complex constellation of developmental abnormalities in humans affecting multiple organ systems such as the eyes, ears, and heart. The CHD7 protein functions to regulate both nucleoplasmic and nucleolar gene expression; however, the respective contributions of each of these functions to proper embryonic development and of their misregulation to CHARGE syndrome is not clear. To this end, we sought out to model changes in CHD7 using the zebrafish as a model for early embryonic development. Targeting of the zebrafish chd7 homolog resulted in developmental abnormalities in multiple organ systems overlapping with those affected in CHARGE syndrome patients. Further investigation in to the chd7 morphant zebrafish revealed global decreases in cellular proliferation accompanied by increased expression of cell-cycle regulator genes. By targeting the expression of fbxl10, a known negative regulator of both rRNA expression and cellular proliferation, we successfully modulated the levels of cellular proliferation and significantly restored the majority of morphological abnormalities. Collectively, these studies indicate that CHD7 plays a significant role in regulating cellular proliferation during embryonic growth and development and provides a novel explanation for the pathogenesis of CHARGE syndrome. To further investigate this possibility, we next sought to test this hypothesis in a human model of embryonic development, or rather, human induced pluripotent stem (iPS) cells. Using CHARGE syndrome patient fibroblast lines, we successfully reprogrammed these cells to a pluripotent state that express several key genes including OCT4 and NANOG. In our initial characterization of these cells, protein expression assays revealed that CHD7 expression levels are severely reduced and are more consistent with a complete loss-of-function rather than a haploinsufficiency. Additionally, CHD7 protein subcellular localization is cell-type dependent. While these results are preliminary, our studies show that the use of CHARGE syndrome patient iPS cell technology can provide an invaluable model to study CHD7 function during development. Furthermore, through their differentiation potential, this model will allow for investigation into the relevance of cellular proliferation defects in the etiology of CHARGE syndrome.
Peter Scacheri, PhD (Advisor)
Ronald Conlon, PhD (Committee Chair)
Peter Harte, PhD (Committee Member)
Brian McDermott, Jr., PhD (Committee Member)
149 p.
Genetics
CHD7; FBXL10; CHARGE syndrome; zebrafish; development; iPS cells

Recommended Citations

Citations

  • Balow, S. A. (2014). Investigation of CHD7 Function in Developmental Models of CHARGE Syndrome [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1396625345

    APA Style (7th edition)

  • Balow, Stephanie. Investigation of CHD7 Function in Developmental Models of CHARGE Syndrome. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1396625345.

    MLA Style (8th edition)

  • Balow, Stephanie. "Investigation of CHD7 Function in Developmental Models of CHARGE Syndrome." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396625345

    Chicago Manual of Style (17th edition)

case1396625345
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© 2014, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.