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Cell Stem Cell. 2016 Feb 4;18(2):214-28. doi: 10.1016/j.stem.2015.11.001. Epub 2015 Nov 25.

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

Author information

1
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
2
Stowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
3
Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Immuno Microenvironment and Disease of the Educational Ministry, Tianjin Medical University, Tianjin, P.R. China.
4
Centre for Stem Cell Research, Christian Medical College, Vellore, 632002, India.
5
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
6
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
7
Department of Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan.
8
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
9
Stowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA. Electronic address: lil@stowers.org.

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.

PMID:
26627594
PMCID:
PMC5545934
DOI:
10.1016/j.stem.2015.11.001
[Indexed for MEDLINE]
Free PMC Article

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