Novel Role for EKLF in Megakaryocyte-Erythroid Differential Lineage Commitment.

Megakaryocytes and erythroid cells are thought to derive from a common progenitor. Although a number of transcriptional regulators are important for this process, they do not explain the bipotential result. We have used gain- and loss-of-function studies, expression profiling, and molecular analyses to show that EKLF, a transcription factor whose crucial role in erythroid gene regulation is well established, plays an unexpected function in the lineage decision between megakaryopoiesis and erythropoiesis. It achieves this by inhibiting the formation of megakaryocytes derived from the common megakaryocyte-erythroid precursor (MEP) cell, while at the same time stimulating erythroid differentiation. Quantitative examination of EKLF expression during hematopoiesis reveals that, unlike genes whose presence is required for establishment of both lineages, EKLF expression is uniquely down-regulated in megakaryocytes after formation of the MEP. Microarray and molecular analyses support these observations and suggest that megakaryocytic inhibition is achieved, at least in part, by EKLF repression of Fli-1 message levels. These results reveal for the first time that EKLF plays a directive role in erythroid and megakaryocyte lineage decisions prior to establishment of the red cell compartment and suggest a model for transcription factor antagonism in MEP differential lineage commitment. Tests as predicted by this model will be discussed.