RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation. 2015

Olga N Kuvardina, and Julia Herglotz, and Stephan Kolodziej, and Nicole Kohrs, and Stefanie Herkt, and Bartosch Wojcik, and Thomas Oellerich, and Jasmin Corso, and Kira Behrens, and Ashok Kumar, and Helge Hussong, and Henning Urlaub, and Joachim Koch, and Hubert Serve, and Halvard Bonig, and Carol Stocking, and Michael A Rieger, and Jörn Lausen
Georg-Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany;

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.

UI MeSH Term Description Entries
D008533 Megakaryocytes Very large BONE MARROW CELLS which release mature BLOOD PLATELETS. Megakaryocyte
D011518 Proto-Oncogene Proteins Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. Cellular Proto-Oncogene Proteins,c-onc Proteins,Proto Oncogene Proteins, Cellular,Proto-Oncogene Products, Cellular,Cellular Proto Oncogene Proteins,Cellular Proto-Oncogene Products,Proto Oncogene Products, Cellular,Proto Oncogene Proteins,Proto-Oncogene Proteins, Cellular,c onc Proteins
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D004920 Erythropoiesis The production of red blood cells (ERYTHROCYTES). In humans, erythrocytes are produced by the YOLK SAC in the first trimester; by the liver in the second trimester; by the BONE MARROW in the third trimester and after birth. In normal individuals, the erythrocyte count in the peripheral blood remains relatively constant implying a balance between the rate of erythrocyte production and rate of destruction. Erythropoieses
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000073942 T-Cell Acute Lymphocytic Leukemia Protein 1 A basic helix-loop-helix transcription factor that plays a critical role in HEMATOPOIESIS and as a positive regulator in the differentiation of ERYTHROID CELLS. Chromosome translocations involving the TAL-1 gene are associated with T-CELL ACUTE LYMPHOCYTIC LEUKEMIA. TAL-1 Protein,TAL1 Transcription Factor,T Cell Acute Lymphocytic Leukemia Protein 1,TAL 1 Protein,Transcription Factor, TAL1
D015672 Erythroid Precursor Cells The cells in the erythroid series derived from MYELOID PROGENITOR CELLS or from the bi-potential MEGAKARYOCYTE-ERYTHROID PROGENITOR CELLS which eventually give rise to mature RED BLOOD CELLS. The erythroid progenitor cells develop in two phases: erythroid burst-forming units (BFU-E) followed by erythroid colony-forming units (CFU-E); BFU-E differentiate into CFU-E on stimulation by ERYTHROPOIETIN, and then further differentiate into ERYTHROBLASTS when stimulated by other factors. Burst-Forming Units, Erythroid,Colony-Forming Units, Erythroid,Erythroid Progenitor Cells,Erythropoietic Progenitor Cells,Erythropoietic Stem Cells,Progenitor Cells, Erythropoietic,Stem Cells, Erythroid,BFU-E,CFU-E,BFU E,BFU-Es,Burst Forming Units, Erythroid,Burst-Forming Unit, Erythroid,CFU E,CFU-Es,Cell, Erythroid Precursor,Cell, Erythroid Progenitor,Cell, Erythroid Stem,Cell, Erythropoietic Progenitor,Cell, Erythropoietic Stem,Cells, Erythroid Precursor,Cells, Erythroid Progenitor,Cells, Erythroid Stem,Cells, Erythropoietic Progenitor,Cells, Erythropoietic Stem,Colony Forming Units, Erythroid,Colony-Forming Unit, Erythroid,Erythroid Burst-Forming Unit,Erythroid Burst-Forming Units,Erythroid Colony-Forming Unit,Erythroid Colony-Forming Units,Erythroid Precursor Cell,Erythroid Progenitor Cell,Erythroid Stem Cell,Erythroid Stem Cells,Erythropoietic Progenitor Cell,Erythropoietic Stem Cell,Precursor Cell, Erythroid,Precursor Cells, Erythroid,Progenitor Cell, Erythroid,Progenitor Cell, Erythropoietic,Progenitor Cells, Erythroid,Stem Cell, Erythroid,Stem Cell, Erythropoietic,Stem Cells, Erythropoietic,Unit, Erythroid Burst-Forming,Unit, Erythroid Colony-Forming,Units, Erythroid Burst-Forming,Units, Erythroid Colony-Forming
D050676 Core Binding Factor Alpha 2 Subunit A transcription factor that dimerizes with the cofactor CORE BINDING FACTOR BETA SUBUNIT to form core binding factor. It contains a highly conserved DNA-binding domain known as the runt domain. Runx1 is frequently mutated in human LEUKEMIAS. AML1A Protein,AML1B Protein,AML1C Protein,AML1D Protein,Acute Myeloid Leukemia 1 Protein,Acute Myeloid Leukemia 1A Protein,Acute Myeloid Leukemia 1B Protein,Acute Myeloid Leukemia 1C Protein,Acute Myeloid Leukemia 1D Protein,Core-Binding Factor Alpha 2 Protein,Pebp2a2 Protein,Runt-Related Transcription Factor 1,Runx1 Protein,Core Binding Factor Alpha 2 Protein,Runt Related Transcription Factor 1
D051741 Kruppel-Like Transcription Factors A family of zinc finger transcription factors that share homology with Kruppel protein, Drosophila. They contain a highly conserved seven amino acid spacer sequence in between their ZINC FINGER MOTIFS. Kruppel-Like Factor,Kruppel-Like Transcription Factor,Kruppel-Like Factors,Factor, Kruppel-Like,Factor, Kruppel-Like Transcription,Kruppel Like Factor,Kruppel Like Factors,Kruppel Like Transcription Factor,Kruppel Like Transcription Factors,Transcription Factor, Kruppel-Like,Transcription Factors, Kruppel-Like

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