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.