ADJACENT DNA ELEMENTS DOMINANTLY RESTRICT THE UBIQUITOUS ACTIVITY OF A NOVEL CHROMATIN-OPENING REGION TO SPECIFIC TISSUES

Locus control regions (LCRs) are thought to provide a dominant tissue- specific open chromatin domain that allows for proper gene regulation by enhancers/silencers and their associated transcription factors. Exp ression of the T-cell receptor alpha (TCR alpha) gene is limited to T cells and its locus exists in different chromatin configurations in ex pressing and nonexpressing cell types. Here we show that eight DNase I -hypersensitive sites in the TCR alpha locus comprise an LCR that conf ers T-cell compartment-specific expression upon a linked heterologous transgene. Removal of the three 5'-most hypersensitive sites of this L CR, containing TCR alpha enhancers/silencers, abolishes tissue-differe ntial chromatin structure and results in transgene expression in all t issues examined. The remaining five DNase I-hypersensitive sites there fore constitute a novel control element possessing a widely active chr omatin-opening function that allows for ubiquitous expression of a lin ked transgene in all transgenic founder mice. Furthermore, these data show that cis-acting elements without inherent LCR activity can domina ntly modulate chromatin structure to determine tissue-specific gene ex pression in vivo.