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

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Issue Date
2016-02Author
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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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.
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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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