Direct and Indirect Mechanisms of Repression Participate in Suppression of T-Cell-Specific Gene Expression in T × L-Cell Hybrids
Expression of tissue-specific genes can be altered upon fusion of mammalian cells of different types. To resolve the genetic basis of this phenomenon and to identify components of the regulatory circuits that are involved, we have established a series of somatic cell hybrids between mouse T cells and L cells. These hybrids have an unusual and interesting phenotype. Unlike many hybrid cells studied, in which the expression of an entire set of tissue-specific genes was coordinately extinguished, in our T × L-cell hybrids only two out of seven T-cell-restricted genes were completely extinguished, whereas the other genes were repressed to various degrees. These hybrids extinguish the production of TCRβ and Thy-1 mRNA, repress the expression of TCRα, GATA-3, TCF-1, and LEF-1 genes to different extents, exhibit small changes in the level of CD3-ɛ mRNA, and continue to express the fibroblast-specific fibronectin gene, and the ets-1 gene. In this study we have evaluated for the first time the molecular mechanisms that underlie the repression of TCRα and TCRβ chain genes in T × L-cell hybrids. We have shown that multiple repression mechanisms, both direct and indirect, contribute to TCRα and TCRβ suppression. Repression of the expression of these genes correlated not only with the downregulation of GATA-3, TCF-1, and LEF-1 transcription factor expression, and with a change in the chromatin structure, but more importantly, with the activation of the silencer activity. Our study provides evidence for the existence of at least two negatively regulating elements, located at the TCRα enhancer-containing fragment and at the silencer region, which are active in our hybrid cells. We have shown that there was no correlation between the levels of GATA-3, TCF-1, and LEF-1 expression versus the level of TCRα mRNA in the independent hybrids. In contrast, both the silencer activity and the ability of the TCRα enhancer to downregulate thymidine kinase (TK) promoter activity were found to be in an inverse correlation with the ability of the different hybrid cells to express TCRα mRNA.
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Document Type: Research Article
Publication date: January 1, 1996
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