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

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 Drosophilaembryogenesis. ZEB also binds to the promoter of pivotal hematopoietic genes (including those encoding interleukin-2, CD4, GATA-3, and α₄-integrin), and mice in which ZEB has been genetically targeted show thymic atrophy, severe defects in lymphocyte differentiation, and increased expression of the α₄-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 etsfamily, 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.

ACKNOWLEDGMENTS

We acknowledge C. Caelles, B. Calabretta, S. Chellappan, T. Genetta, A. Giordano, E. Harlow, T. Kadesch, R. Kopan, S. J. Korsmeyer, T. Lipsick, D. Livingston, J. Molkentin, E. Olson, G. Tomaselli, and H. Weintraub for providing us with plasmids, cell lines, and antibodies.

A.A.P. was supported by the Leukemia Society of America. This work was funded by grants from the National Institutes of Health to D.C.D.