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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Antigens, CD / metabolism
  • Calcium-Binding Proteins
  • Fetus / metabolism
  • Genetic Loci*
  • Genomic Imprinting
  • HEK293 Cells
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Liver / cytology
  • Liver / embryology
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mutation / genetics
  • Organelle Biogenesis
  • Phosphatidylinositol 3-Kinases / metabolism*
  • RNA, Long Noncoding / metabolism*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism*


  • Antigens, CD
  • Calcium-Binding Proteins
  • Dlk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • MEG3 non-coding RNA, mouse
  • MicroRNAs
  • RNA, Long Noncoding
  • Reactive Oxygen Species
  • TOR Serine-Threonine Kinases
  • Sirolimus
  • Acetylcysteine