Independent repressor domains in ZEB regulate muscle and T-cell differentiation

ZEE is a zinc finger-homeodomain protein that represses transcription by bi nding to a subset of E-box sequences. ZEE inhibits muscle differentiation i n mammalian systems, and its Drosophila orthologue, zfh-1, inhibits somatic and cardiac muscle differentiation during Drosophila embryogenesis. ZEE al so binds to the promoter of pivotal hematopoietic genes (including those en coding interleukin-2, CD4, GATA-3, and alpha(4)-integrin), and mice in whic h ZEE has been genetically targeted show thymic atrophy, severe defects in lymphocyte differentiation, and increased expression of the alpha(4)-integr in and CD4. Here, we demonstrate that ZEB contains separate repressor domai ns which function in T lymphocytes and muscle, respectively. The most C-ter minal domain inhibits muscle differentiation in mammalian cells by specific ally blocking the transcriptional activity of the myogenic factor MEF2C. Th e more N-terminal domain blocks activity of hematopoietic transcription fac tors such as c-myb, members of the ets family, and TFE-III. Our results dem onstrate that ZEE has evolved with two independent repressor domains which target distinct sets of transcription factors and function in different tis sues.