title: C/EBPα is required for long-term self-renewal and lineage priming of hematopoietic stem cells and for the maintenance of epigenetic configurations in multipotent progenitors.
abstract: Transcription factors are key regulators of hematopoietic stem cells (HSCs) and act through their ability to bind DNA and impact on gene transcription. Their functions are interpreted in the complex landscape of chromatin, but current knowledge on how this is achieved is very limited. C/EBPα is an important transcriptional regulator of hematopoiesis, but its potential functions in HSCs have remained elusive. Here we report that C/EBPα serves to protect adult HSCs from apoptosis and to maintain their quiescent state. Consequently, deletion of Cebpa is associated with loss of self-renewal and HSC exhaustion. By combining gene expression analysis with genome-wide assessment of C/EBPα binding and epigenetic configurations, we show that C/EBPα acts to modulate the epigenetic states of genes belonging to molecular pathways important for HSC function. Moreover, our data suggest that C/EBPα acts as a priming factor at the HSC level where it actively promotes myeloid differentiation and counteracts lymphoid lineage choice. Taken together, our results show that C/EBPα is a key regulator of HSC biology, which influences the epigenetic landscape of HSCs in order to balance different cell fate options.
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Marie S
authors.initials: MS
authors.lastname: Hasemann
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Felicia K B
authors.initials: FK
authors.lastname: Lauridsen
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; The Bioinformatic Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Johannes
authors.initials: J
authors.lastname: Waage
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Janus S
authors.initials: JS
authors.lastname: Jakobsen
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anne-Katrine
authors.initials: AK
authors.lastname: Frank
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mikkel B
authors.initials: MB
authors.lastname: Schuster
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; The Bioinformatic Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Rapin
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; The Bioinformatic Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Frederik O
authors.initials: FO
authors.lastname: Bagger
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Hoppe
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; The Bioinformatic Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Bo T
authors.initials: BT
authors.lastname: Porse
mesh_terms: D000818:Animals; D017209:Apoptosis; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage; D049109:Cell Proliferation; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha