title: 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.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Ortiz
authors.forename: D
authors.initials: D
authors.lastname: Cado
authors.forename: V
authors.initials: V
authors.lastname: Chen
authors.forename: P W
authors.initials: PW
authors.lastname: Diaz
authors.forename: A
authors.initials: A
authors.lastname: Winoto
mesh_terms: D001483:Base Sequence; D002843:Chromatin / Q000737:chemistry / Q000235:genetics*; D003850:Deoxyribonuclease I / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000235:genetics; D005914:Globins / Q000235:genetics; D008957:Models, Genetic; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D012260:Ribonucleases / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors; D019076:Transgenes / Q000235:genetics
chemical_list: D002843:Chromatin; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014157:Transcription Factors; D005914:Globins; D012260:Ribonucleases; D003850:Deoxyribonuclease I