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 KLF1 and FLI1 has such a decisive role. However, how this antagonism is resolved during lineage specification is poorly understood. We found that RUNX1 inhibits erythroid differentiation of murine megakaryocytic/erythroid progenitors (MEPs) 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 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, which represses the erythroid gene expression program.
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