RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation.
The activity of antagonizing transcription factors represents a mechanistic paradigm of bidirectional lineage-fate control during hematopoiesis. At the megakaryocytic/erythroid bifurcation, the cross-antagonism of krueppel-like factor 1 (KLF1) and friend leukemia integration 1 (FLI1) has such a decisive role. However, how this antagonism is resolved during lineage specification is poorly understood. We found that runt-related transcription factor 1 (RUNX1) inhibits erythroid differentiation of murine megakaryocytic/erythroid progenitors and primary human CD34(+) progenitor cells. We show that RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation by epigenetic repression of the erythroid master regulator KLF1. RUNX1 binding to the KLF1 locus is increased during megakaryocytic differentiation and counterbalances the activating role of T-cell acute lymphocytic leukemia 1 (TAL1). We found that corepressor recruitment by RUNX1 contributes to a block of the KLF1-dependent erythroid gene expression program. Our data indicate that the repressive function of RUNX1 influences the balance between erythroid and megakaryocytic differentiation by shifting the balance between KLF1 and FLI1 in the direction of FLI1. Taken together, we show that RUNX1 is a key player within a network of transcription factors that represses the erythroid gene expression program.
Georg-Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany;
Olga N
ON
Kuvardina
Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
Julia
J
Herglotz
Georg-Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany;
Stephan
S
Kolodziej
Georg-Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany;
Nicole
N
Kohrs
Georg-Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany;
Stefanie
S
Herkt
Department of Medicine, Hematology/Oncology, Johann-Wolfgang-Goethe University, Frankfurt am Main, Germany;
Bartosch
B
Wojcik
Department of Medicine, Hematology/Oncology, Johann-Wolfgang-Goethe University, Frankfurt am Main, Germany; German Cancer Consortium, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany;
Thomas
T
Oellerich
Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany;
Jasmin
J
Corso
Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
Kira
K
Behrens
Georg-Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany;
Ashok
A
Kumar
Georg-Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany;
Helge
H
Hussong
Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany;
Henning
H
Urlaub
Georg-Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany;
Joachim
J
Koch
Department of Medicine, Hematology/Oncology, Johann-Wolfgang-Goethe University, Frankfurt am Main, Germany; German Cancer Consortium, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany;
Hubert
H
Serve
German Red Cross Blood Service and Institute for Transfusion Medicine and Immunohematology, Johann-Wolfgang-Goethe University, Frankfurt am Main, Germany; and.
Halvard
H
Bonig
Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
Carol
C
Stocking
Department of Medicine, Hematology/Oncology, Johann-Wolfgang-Goethe University, Frankfurt am Main, Germany; German Cancer Consortium, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany; LOEWE Center for Cell and Gene Therapy, Frankfurt, Germany.
Michael A
MA
Rieger
Georg-Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany;
Jörn
J
Lausen
D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D034061:Thrombopoiesis / Q000502:physiology*
D018952:Antigens, CD34; D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C493728:RUNX1 protein, human; C080774:erythroid Kruppel-like factor; C067143:TAL1 protein, human