title: ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation.
abstract: The balance between self-renewal and differentiation is crucial for the maintenance of hematopoietic stem cells (HSCs). Whereas numerous gene regulatory factors have been shown to control HSC self-renewal or drive their differentiation, we have relatively few insights into transcription factors that serve to restrict HSC differentiation. In the present work, we identify ETS (E-twenty-six)-related gene (ERG) as a critical factor protecting HSCs from differentiation. Specifically, loss of Erg accelerates HSC differentiation by >20-fold, thus leading to rapid depletion of immunophenotypic and functional HSCs. Molecularly, we could demonstrate that ERG, in addition to promoting the expression of HSC self-renewal genes, also represses a group of MYC targets, thereby explaining why Erg loss closely mimics Myc overexpression. Consistently, the BET domain inhibitor CPI-203, known to repress Myc expression, confers a partial phenotypic rescue. In summary, ERG plays a critical role in coordinating the balance between self-renewal and differentiation of HSCs.
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Kasper Jermiin
authors.initials: KJ
authors.lastname: Knudsen
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Matilda
authors.initials: M
authors.lastname: Rehn
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Marie Sigurd
authors.initials: MS
authors.lastname: Hasemann
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; The Bioinformatic Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Rapin
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; The Bioinformatic Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Frederik Otzen
authors.initials: FO
authors.lastname: Bagger
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Ewa
authors.initials: E
authors.lastname: Ohlsson
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Anton
authors.initials: A
authors.lastname: Willer
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Anne-Katrine
authors.initials: AK
authors.lastname: Frank
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Søndergaard
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Johan
authors.initials: J
authors.lastname: Jendholm
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Lina
authors.initials: L
authors.lastname: Thorén
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.affiliation: Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, SE-22184 Lund, Sweden;
authors.forename: Justyna
authors.initials: J
authors.lastname: Rak
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Department of Hematology, Skånes University Hospital, University of Lund, SE-22185 Lund, Sweden.
authors.forename: Kim
authors.initials: K
authors.lastname: Theilgaard-Mönch
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
authors.forename: Bo Torben
authors.initials: BT
authors.lastname: Porse
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG
chemical_list: C531115:ERG protein, mouse; D015513:Oncogene Proteins; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG
keywords: CPI-203; ERG; MYC; differentiation; hematopoietic stem cell; self-renewal