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    The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism

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    Qian_CellStemCell_2016.pdf (3.572Mb)
    Issue Date
    2016-02
    Author
    Qian, Pengxu
    He, Xi C.
    Paulson, Ariel
    Li, Zhenrui
    Tao, Fang
    Perry, John M.
    Guo, Fengli
    Zhao, Meng
    Zhi, Lei
    Venkatraman, Aparna
    Haug, Jeffrey S.
    Parmely, Tari
    Li, Hua
    Dobrowsky, Rick T.
    Ding, Weng-Xing
    Kono, Tomohiro
    Ferguson-Smith, Anne C.
    Li, Linheng
    Publisher
    Elsevier
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    Copyright © 2016 Elsevier Inc. All rights reserved.
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    Abstract
    The mammalian imprinted Dlk1-Gtl2 locus produces multiple non-coding RNAs (ncRNAs) from the maternally inherited allele, including the largest miRNA cluster in the mammalian genome. This locus has characterized functions in some types of stem cell, but its role in hematopoietic stem cells (HSCs) is unknown. Here, we show that the Dlk1-Gtl2 locus plays a critical role in preserving long-term repopulating HSCs (LT-HSCs). Through transcriptome profiling in 17 hematopoietic cell types, we found that ncRNAs expressed from the Dlk1-Gtl2 locus are predominantly enriched in fetal liver HSCs and the adult LT-HSC population and sustain long-term HSC functionality. Mechanistically, the miRNA mega-cluster within the Dlk1-Gtl2 locus suppresses the entire PI3K-mTOR pathway. This regulation in turn inhibits mitochondrial biogenesis and metabolic activity and protects LT-HSCs from excessive reactive oxygen species (ROS) production. Our data therefore show that the imprinted Dlk1-Gtl2 locus preserves LT-HSC function by restricting mitochondrial metabolism.
    URI
    http://hdl.handle.net/1808/24965
    DOI
    https://doi.org/10.1016/j.stem.2015.11.001
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Qian, P., He, X. C., Paulson, A., Li, Z., Tao, F., Perry, J. M., … Li, L. (2016). The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism. Cell Stem Cell, 18(2), 214–228. http://doi.org/10.1016/j.stem.2015.11.001

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    KU Libraries
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    785-864-8983

    KU Libraries
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    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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