Open AccessSynergism between hypersensitive sites confers long-range gene activation by the β-globin locus control region
Author(s) -
Emery H. Bresnick,
Lina E. Tze
Publication year - 1997
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.94.9.4566
Subject(s) - locus control region , enhancer , chromatin , hypersensitive site , globin , biology , microbiology and biotechnology , transcription (linguistics) , enhancer rnas , dnase i hypersensitive site , locus (genetics) , gene , dna , deoxyribonuclease i , promoter , transcription factor , genetics , gene expression , linguistics , philosophy , base sequence
The human β-globin locus control region (LCR) consists of four erythroid-specific DNaseI hypersensitive sites (HSs) at the 5′ end of the β-globin cluster. The LCR functions over a long distance on chromosome 11 to regulate transcription and replication of the β-globin genes. To determine whether the HSs function independently or as an integrated unit, we analyzed the requirements for long-range transcriptional activation. If the HSs function independently, individual HSs would be expected to have long-range activity. In contrast, if long-range activity requires multiple HSs, individual HSs would have a limited functional distance. HS2, HS3, and a miniLCR containing multiple HSs, were separated from a γ-globin promoter by fragments of phage λ DNA. After stable transfection into K562 cells, HS2 had strong enhancer activity, but only when positioned close to the promoter. HS3 also had strong enhancer activity, although it was weaker than HS2 and more sensitive to the spacer DNA. The miniLCR had the strongest enhancer activity and functioned even at a distance of 7.3 kb. A model is proposed in which synergistic interactions between HSs confer long-range activation by creating astable LCR nucleoprotein structure, which is competent for recruiting chromatin-modifying enzymes. These enzymes would mediate the well-characterized activity of the LCR to modulate chromatin structure.