title: Polycomb group ring finger 1 cooperates with Runx1 in regulating differentiation and self-renewal of hematopoietic cells.
abstract: The transcription factor runt-related transcription factor 1 (Runx1) is essential for the establishment of definitive hematopoiesis during embryonic development. In adult blood homeostasis, Runx1 plays a pivotal role in the maturation of lymphocytes and megakaryocytes. Furthermore, Runx1 is required for the regulation of hematopoietic stem and progenitor cells. However, how Runx1 orchestrates self-renewal and lineage choices in combination with other factors is not well understood. In the present study, we describe a genome-scale RNA interference screen to detect genes that cooperate with Runx1 in regulating hematopoietic stem and progenitor cells. We identify the polycomb group protein Pcgf1 as an epigenetic regulator involved in hematopoietic cell differentiation and show that simultaneous depletion of Runx1 and Pcgf1 allows sustained self-renewal while blocking differentiation of lineage marker-negative cells in vitro. We found an up-regulation of HoxA cluster genes on Pcgf1 knock-down that possibly accounts for the increase in self-renewal. Moreover, our data suggest that cells lacking both Runx1 and Pcgf1 are blocked at an early progenitor stage, indicating that a concerted action of the transcription factor Runx1, together with the epigenetic repressor Pcgf1, is necessary for terminal differentiation. The results of the present study uncover a link between transcriptional and epigenetic regulation that is required for hematopoietic differentiation.
authors.affiliation: University Hospital Carl Gustav Carus and Medical Faculty, University of Technology Dresden, Dresden, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Ross
authors.forename: Anna K
authors.initials: AK
authors.lastname: Sedello
authors.forename: Gabriele Putz
authors.initials: GP
authors.lastname: Todd
authors.forename: Maciej
authors.initials: M
authors.lastname: Paszkowski-Rogacz
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Bird
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Tatyana
authors.initials: T
authors.lastname: Grinenko
authors.forename: Kira
authors.initials: K
authors.lastname: Behrens
authors.forename: Nina
authors.initials: N
authors.lastname: Hubner
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.forename: Claudia
authors.initials: C
authors.lastname: Waskow
authors.forename: Carol
authors.initials: C
authors.lastname: Stocking
authors.forename: Frank
authors.initials: F
authors.lastname: Buchholz
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002455:Cell Division; D002478:Cells, Cultured / Q000166:cytology; D047369:Chromatin Immunoprecipitation; D003114:Colony-Forming Units Assay; D050676:Core Binding Factor Alpha 2 Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D063150:Polycomb Repressive Complex 1; D034741:RNA, Small Interfering / Q000494:pharmacology; D011828:Radiation Chimera; D060888:Real-Time Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D014161:Transduction, Genetic
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C570527:Pcgf1 protein, mouse; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C493726:Runx1 protein, mouse; D063150:Polycomb Repressive Complex 1