title: The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism.
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.
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Pengxu
authors.initials: P
authors.lastname: Qian
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Xi C
authors.initials: XC
authors.lastname: He
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Paulson
authors.affiliation: 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.
authors.forename: Zhenrui
authors.initials: Z
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Fang
authors.initials: F
authors.lastname: Tao
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Perry
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Fengli
authors.initials: F
authors.lastname: Guo
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhi
authors.affiliation: Centre for Stem Cell Research, Christian Medical College, Vellore, 632002, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Venkatraman
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Haug
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Tari
authors.initials: T
authors.lastname: Parmely
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Rick T
authors.initials: RT
authors.lastname: Dobrowsky
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
authors.affiliation: Department of Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kono
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
authors.affiliation: 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.
authors.forename: Linheng
authors.initials: L
authors.lastname: Li
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002135:Calcium-Binding Proteins; D005333:Fetus / Q000378:metabolism; D056426:Genetic Loci; D018392:Genomic Imprinting; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000196:embryology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D001678:Organelle Biogenesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000111:Acetylcysteine; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D062085:RNA, Long Noncoding; D017382:Reactive Oxygen Species; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C512925:Dlk1 protein, mouse; C422882:MEG3 non-coding RNA, mouse