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    Chromosome 21 Dosage Effects in Down Syndrome by “Trisomy Silencing” Reveals Impairment of Angiogenic and Neurogenic Processes

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    MoonJennifer_Thesis_FinalDraft ...
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    Authors
    Moon, Jennifer Eunmi
    Faculty Advisor
    Jeanne B Lawrence, PhD
    Academic Program
    Cell Biology
    UMass Chan Affiliations
    Neurology
    Document Type
    Doctoral Dissertation
    Publication Date
    2021-05-07
    Keywords
    XIST
    Down syndrome
    Trisomy 21
    angiogenesis
    stem cell biology
    differentiation
    development
    Cell Biology
    Developmental Biology
    Genetics
    
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    Abstract
    Maintenance of gene dosage is important for proper cellular function and development, as evidenced by the natural silencing of one X-chromosome in mammalian females, and by the embryonic lethality of most autosomal aneuploidy. A notable exception is Down syndrome (DS), which occurs in 1/700 newborns. It has been known for 50+ years that DS is caused by trisomy for chromosome 21 (chr21), yet biological understanding remains wanting; even what cell types and pathways are impacted by chr21 dosage has remained unclear. Given the complexity of DS, better experimental approaches have been needed. This thesis advances understanding of DS pathobiology using an innovative approach that translates the X-inactivation mechanism via the XIST gene, to an inducible system to “silence trisomy” in DS patient-derived iPSCs and their differentiated derivatives. I investigated the most immediate and direct effects of silencing trisomy on mRNAs genome-wide. Initial studies revealed trisomy 21 (T21) impairs early developmental pathways for two major cell type processes: neurogenesis and, surprisingly, angiogenesis. Further analysis of endothelial cells showed chr21 overexpression reduces pathways relating to cell migration, projection, and signaling, and functional assays showed delayed response to angiogenic cues causing a deficit in microvessel formation. The previously unknown cell-autonomous effect of T21 on angiogenesis has broad significance for systems impacted, including brain and heart development, and comorbidities throughout life such as early-onset Alzheimer’s disease. This work also has implications for understanding of dosage sensitivity and genome balance, a fundamental but poorly understood aspect of genome biology.
    DOI
    10.13028/b13b-9x97
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31384
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/b13b-9x97
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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