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ABSTRACT
We have previously identified a transcriptional silencer that is critical for proper expression of the CD4 gene during T-cell development. Here we report that the Hairy/Enhancer of Split homologue HES-1, a transcription factor in the lin12/Notch signaling pathway, binds to an important functional site in the CD4 silencer. Overexpression of HES-1 leads to the silencer site-dependent repression of CD4 promoter and enhancer function as well as the downregulation of endogenous CD4 expression in CD4+ CD8−TH cells. Interestingly, overexpression of an activated form of Notch1 (NotchIC) leads to the repression of CD4 promoter and enhancer function both in the presence and absence of the silencer. NotchIC-mediated CD4 silencer function is not affected by the deletion of the HES-1-binding site, indicating that multiple factors binding to CD4 transcriptional control elements are responsive to signaling from this pathway, including other silencer-binding factors. Taken together, these data are consistent with the hypothesis that the lin12/Notch signaling pathway is important in thymic development and provide a molecular mechanism via the control of CD4 gene expression in which the lin12/Notch pathway affects T-cell developmental fate.
ACKNOWLEDGMENTS
We thank Sophia Sarafova and Dan Ng for advice and technical assistance, Ryoichiro Kageyama for the HES-1 cDNA clone, Kevin Fitzgerald for the GST–HES-1 fusion protein, Jan Kitajewski and GuangYu Wu for the HES-1-transfected 293T extracts, Chris Roman for the EF-1α expression plasmid, and Kathryn Calame, Kevin Fitzgerald, Max Gottesman, Iva Greenwald, Jan Kitajewski, Andrew Henderson, Gary Struhl, and the members of the Siu lab for helpful discussions and critical reading of the manuscript.
This work was supported by grants from the American Cancer Society (JFRA-484 and RPG-98-185-01-CIM) and the Irma T. Hirschl-Monique Caulier Weill Charitable Trust to G.S. H.K.K. is supported by NIH training grant T32AI07525.