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    Ectopic expression and knocking-down of LINE-1 mRNA in human mesenchymal stem cells: impact on in vitro osteogenic and adipogenic differentiation

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    Nazerke Atinbayeva Thesis
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    Type
    Thesis
    Authors
    Atinbayeva, Nazerke cc
    Advisors
    Orlando, Valerio cc
    Committee members
    Merzaban, Jasmeen cc
    Mahfouz, Magdy M. cc
    Program
    Bioscience
    KAUST Department
    Biological and Environmental Science and Engineering (BESE) Division
    Date
    2018-05
    Embargo End Date
    2021-07-31
    Permanent link to this record
    http://hdl.handle.net/10754/627885
    
    Metadata
    Show full item record
    Access Restrictions
    At the time of archiving, the student author of this thesis opted to temporarily restrict access to it. The full text of this thesis became available to the public after the expiration of the embargo on 2021-07-31.
    Abstract
    There are two classes of transposable elements: DNA transposons and retrotransposons. DNA transposons spread in the genome by “cut and paste” mechanism. In contrast, retrotransposons use copy and paste strategy involving RNA and retrotranscriptase mediated mechanism; these include long interspersed nuclear elements-1 (LINE-1, L1) and short interspersed nuclear elements (SINE). In mammals, in order to maintain genome integrity both types of transposons are tightly repressed. However, some copies of retrotransposons are still active in germ cells contributing to natural variation. Surprisingly, recent reports indicate that also somatic cells support L1 reactivation in early development, in particular in the brain leading to mosaicism. However, whether L1 retrotransposition is a part of other cell lineage developmental programs and its functional significance in the context of cell differentiation remain to be elucidated. To address this question, I investigated whether L1 retrotransposition was occurring during in vitro osteogenic and adipogenic differentiation of bone marrow derived human mesenchymal stem cells (hMSCs). Interestingly, clinical observations have revealed loss of bone density in HIV-infected individuals treated with nucleoside analogs that inhibit HIV retrotranscriptase, as well as the endogenous one encoded by L1s. This observation made us to hypothesize that transposable elements played a positive role in post-natal bone homeostasis. I found that while adipogenesis is “retrotransposition free”, osteogenic differentiation is a “retrotransposition-prone” process and its inhibition blocks its genetic program. Indeed, L1 DNA content does not change during adipogenic differentiation and that of retrotranscriptase does not have any effect on the acquisition of a terminally differentiated phenotype. In contrast, soon after MSCs commitment into pre-osteoblasts, L1 retrotransposable elements increase their expression and actively transpose. Inhibition of retrotransposition and knock down of L1 mRNA strongly impairs matrix deposition. Moreover, I forced L1 expression in in vitro adipogenesis, by directly delivering L1 mRNA to the cells. Interestingly, overexpression of L1 elements was detrimental for in vitro adipogenesis. Then, I performed loss of function experiments in osteogenesis by directly targeting and degrading the L1 endogenous transcript. This experiment confirmed the positive role of L1 reactivation in the osteogenic context, suggesting also a possible role for L1 RNA, distinct from retrotransposition.
    Citation
    Atinbayeva, N. (2018). Ectopic expression and knocking-down of LINE-1 mRNA in human mesenchymal stem cells: impact on in vitro osteogenic and adipogenic differentiation. KAUST Research Repository. https://doi.org/10.25781/KAUST-0N5G6
    DOI
    10.25781/KAUST-0N5G6
    ae974a485f413a2113503eed53cd6c53
    10.25781/KAUST-0N5G6
    Scopus Count
    Collections
    Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program; MS Theses

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