Independent Repressor Domains in ZEB Regulate Muscle and T-Cell Differentiation

Abstract

ABSTRACT ZEB is a zinc finger-homeodomain protein that represses transcription by binding to a subset of E-box sequences. ZEB inhibits muscle differentiation in mammalian systems, and its Drosophila orthologue, zfh-1 , inhibits somatic and cardiac muscle differentiation during Drosophila embryogenesis. ZEB also binds to the promoter of pivotal hematopoietic genes (including those encoding interleukin-2, CD4, GATA-3, and α 4 -integrin), and mice in which ZEB has been genetically targeted show thymic atrophy, severe defects in lymphocyte differentiation, and increased expression of the α 4 -integrin and CD4. Here, we demonstrate that ZEB contains separate repressor domains which function in T lymphocytes and muscle, respectively. The most C-terminal domain inhibits muscle differentiation in mammalian cells by specifically blocking the transcriptional activity of the myogenic factor MEF2C. The more N-terminal domain blocks activity of hematopoietic transcription factors such as c- myb , members of the ets family, and TFE-III. Our results demonstrate that ZEB has evolved with two independent repressor domains which target distinct sets of transcription factors and function in different tissues.