C-MYB AND ETS PROTEINS SYNERGIZE TO OVERCOME TRANSCRIPTIONAL REPRESSION BY ZEB

The Zfh family of zinc finger/homeodomain proteins was first identifie d in Drosophila where it is required for differentiation of tissues su ch as the central nervous system and muscle, ZEB, a vertebrate homolog of Zfh-1, binds a subset of E boxes and blocks myogenesis through tra nscriptional repression of muscle genes, We present evidence here that ZEB also has an important role in controlling hematopoietic gene tran scription, Two families of transcription factors that are required for normal hematopoiesis are c-Myb and Ets. These factors act synergistic ally to activate transcription, and this synergy is required for trans cription of at least several important hematopoietic genes. ZEB blocks the activity of c-Myb and Ets individually, but together the factors synergize to resist this repression. Such repression imposes a require ment for both c-Myb and Ets for transcriptional activity, providing on e explanation for why synergy between these factors is important. The balance between repression by ZEB and transcriptional activation by c- Myb/Ets provides a flexible regulatory mechanism for controlling gene expression in hematopoietic cells. We demonstrate that one target of t his positive/negative regulation in vivo is the alpha 4 integrin, whic h play a key role in normal hematopoiesis and function of mature leuko cytes.