Adjacent DNA elements dominantly restrict the ubiquitous activity of a novel chromatin-opening region to specific tissues

Abstract

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. Expression of the T-cell receptor alpha (TCR alpha) gene is limited to T cells and its locus exists in different chromatin configurations in expressing and nonexpressing cell types. Here we show that eight DNase I-hypersensitive sites in the TCR alpha locus comprise an LCR that confers T-cell compartment-specific expression upon a linked heterologous transgene. Removal of the three 5'-most hypersensitive sites of this LCR, containing TCR alpha enhancers/silencers, abolishes tissue-differential chromatin structure and results in transgene expression in all tissues examined. The remaining five DNase I-hypersensitive sites therefore constitute a novel control element possessing a widely active chromatin-opening function that allows for ubiquitous expression of a linked transgene in all transgenic founder mice. Furthermore, these data show that cis-acting elements without inherent LCR activity can dominantly modulate chromatin structure to determine tissue-specific gene expression in vivo.